Sulfonyl piperidine derivatives and their use for treating prokineticin mediated diseases

ABSTRACT

The present invention provides compounds of formula (I) and pharmaceutically acceptable salts thereof: (I) in which m, n, W, X, Y, Z, R 1 , R 2 , R 3  and R 4  are as defined in the specification, for use in the treatment or prevention of a diseases o conition mediated by a prokineticin, such as psychiatric and neurological conditions.

The present invention relates to the use of piperidine derivatives intherapy, particularly for the treatment or prevention of psychiatric andneurological conditions.

Prokineticins are cysteine-rich regulatory peptides that are thought toexert signaling activity via two highly conserved G protein-coupledreceptors (GPCR), the prokineticin receptor 1 (PKR1 or PROKR1) and theprokineticin receptor 2 (PKR2 or PROKR2), that belong to the7-transmembrane domain, G protein-coupled receptor (GPCR) superfamily.

Prokineticin receptor 1 (also known as GPR73) shows 87% homology toProkineticin Receptor 2 (also known as GPR73L1). Prokineticins (PK1 andPK2) contain 86 and 81 amino acids respectively, sharing 45% amino acididentity. Both prokineticins activate the two prokineticin receptors,PKR1 and PKR2, with similar potency.

PKR1 receptors couple to G_(q)/G₁₁ proteins leading to phospholipase Cactivation, inositol phosphate production and calcium mobilization. Inaddition, activation of the mitogen-activated protein kinase (MAPK)pathways has also been described.

PKR1 is broadly distributed throughout peripheral tissues including theintestinal tract, testis, uterus, lung, mouse dorsal root ganglia,macrophage, bone, heart, rectum, white adipose and peripheral bloodleukocytes. In addition, the receptor is expressed in the brainparticularly in olfactory regions as well as in dorsal root ganglion(DRG) neurons, house hippocampus, dentate gyms, cerebellar cortex,cerebral cortex, human hippocampus, amygdala, medulla oblongata andspinal cord.

Prokineticins were originally identified as potent agents mediating gutmotility, but were later shown to promote angiogenesis in steroidogenicglands (e.g. adrenal gland), heart and reproductive systems. They alsomodulate neurogenesis, circadian rhythms, nociception, haematopoiesis aswell as the immune response. Prokineticins are thought to be associatedwith pathologies of the reproductive and nervous systems, myocardialinfarction and tumorigenesis.

Consequently, antagonisim of the functions of the prokineticins may haveutility in the treatment of disorders or diseases includinggastrointestinal motility, angiogenesis, hematopoiesis, diabetes (e.g.as described in International Patent Application Publication No. WO2010/077976) and pain (e.g. as described in International PatentApplication Publication No. WO 2007/079214).

We have now discovered a new class of compounds that are prokineticinreceptor modulators which have desirable activity profiles. Thecompounds of this invention have beneficial potency, selectivity and/orpharmacokinetic properties.

In accordance with the present invention, there is therefore provided acompound of formula (I)

or a pharmaceutically acceptable salt thereof for use in therapy, inparticular for treating a disease or condition mediated by aprokineticin, specifically prokineticin 1 (PK1) and/or prokineticin 2(PK2), wherein in formula (I)

-   -   W, X, Y and Z each independently represent N, NH or CH, with the        proviso that W, X, Y and Z do not each simultaneously represent        a moiety CH;    -   m is 0, 1, 2 or 3;    -   each R¹ independently represents halogen, cyano, C₁-C₆ alkoxy,        C₁-C₆ alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆        alkylthio, C₁-C₆ alkylcarbonyl, or C₁-C₆ alkyl optionally        substituted by carboxyl or C₁-C₆ alkoxycarbonyl;    -   n is 0, 1, 2, 3 or 4;    -   each R² independently represents halogen, cyano, carboxyl,        hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆ alkyl or a        5- to 9-membered heterocyclic ring system;    -   R³ represents an oxygen or sulphur atom, or a group C═O, NR⁵ or        CR⁶R⁷;    -   R⁵ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R⁶ and R⁷ each independently represent a hydrogen or halogen        atom or cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆        alkoxyC₁-C₆ alkyl or a 5- to 9-membered heterocyclic ring        system;    -   R⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, hydroxyl,        cyano, oxo (═O), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulphinyl, C₁-C₆        alkylsulphonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonyloxy,        C₁-C₆ alkoxycarbonyl, amino (—NH₂), —CON(R⁸)₂, C₁-C₆ alkylamino,        di-(C₁-C₆ alkyl)amino, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy or        C₃-C₆ cycloalkylmethyl; and    -   each R⁸ independently represents a hydrogen atom or a C₁-C₆        alkyl group.

Certain compounds of formula (I) are novel compounds. Therefore thepresent invention further provides a compound of formula (Ia), or apharmaceutically acceptable salt thereof,

wherein

-   -   W¹, X¹, Y¹ and Z¹ each independently represent N, NH or CH, with        the proviso that W¹, X¹, Y¹ and Z¹ do not each simultaneously        represent a moiety CH;    -   p is 0, 1, 2 or 3;    -   each R¹¹ independently represents halogen, cyano, C₁-C₆ alkoxy,        C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆        alkylcarbonyl, or C₁-C₆ alkyl optionally substituted by carboxyl        or C₁-C₆ alkoxycarbonyl;    -   q is 0, 1, 2, 3 or 4;    -   each R¹² independently represents halogen, cyano, carboxyl,        hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆        hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆ alkyl or a        5- to 9-membered heterocyclic ring system;    -   R¹³ represents an oxygen atom, or a group C═O, NR¹⁵ or CR¹⁶R¹⁷,        with the provisos that (i) when R¹³ represents CO or NH and ring        A represents pyrazol-4-yl or imidazol-4-yl, then p must be 3 and        R¹⁴ represents a substituted 6- to 10-membered aromatic or        heteroaromatic ring system, and (ii) when R¹³ represents CH₂ and        ring A represents pyrazol-4-yl or imidazol-4-yl, then either p        is 3, or, p is 2 and q is at least 1;    -   R¹⁵ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁶ and R¹⁷ each independently represent a hydrogen or halogen        atom or cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,        C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆        alkoxyC₁-C₆ alkyl or a 5- to 9-membered heterocyclic ring        system;    -   R¹⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, hydroxyl,        cyano, oxo (═O), C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆ alkynyl,        C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆        haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulphinyl, C₁-C₆        alkylsulphonyl, C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonyloxy,        C₁-C₆ alkoxycarbonyl, amino (—NH₂), —CON(R¹⁸)₂, C₁-C₆        alkylamino, di-(C₁-C₆ alkyl)amino, C₃-C₆ cycloalkyl, C₃-C₆        cycloalkyloxy or C₃-C₆ cycloalkylmethyl; and    -   each R¹⁸ independently represents a hydrogen atom or a C₁-C₆        alkyl group; but excluding the following compounds:

-   1)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,

-   2)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-fluorophenoxyl)piperidine,

-   3)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methoxyphenoxyl)piperidine,

-   4) 1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenoxypiperidine,

-   5)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(3-ethylphenoxyl)piperidine,

-   6) 4-phenoxy-1-(1H-pyrazol-4-ylsulfonyl)piperidine,

-   7)    4-(3-chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,

-   8)    [1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-methoxyphenyl)methanone,

-   9)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2-methylphenoxyl)piperidine,

-   10)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[[2-(trifluoromethyl)phenyl]methyl]-4-piperidinemethanol,

-   11)    1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinecarboxylic    acid, ethyl ester,

-   12)    4-[[1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl]oxy]benzonitrile,

-   13)    N-(2-methylphenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidineamine,

-   14)    1-[[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl]-4-(4-fluorophenoxyl)piperidine,

-   15)    4-(3-fluorophenoxy)-1-[(3-methyl-1-propyl-1H-pyrazol-4-yl)sulfonyl]piperidine,

-   16)    1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(2-fluorophenoxyl)piperidine,

-   17)    1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,

-   18)    1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(phenylmethyl)piperidine,

-   19)    1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,

-   20)    (4-(4-Methoxybenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,

-   21) (4-(4-Chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)    sulfonyl)piperidin-4-yl)methanol,

-   22)    1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinemethanol,

-   23)    4-(phenylmethyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,

-   24)    [1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-fluorophenyl)methanone,    and

-   25) 2-[[1-[3,5-dimethyl-1H-pyrazol-4-yl)    sulfonyl]-4-piperidinyl]oxy]pyrazine.

In the context of the present specification, unless otherwise stated, analkyl, alkenyl or alkynyl substituent group or an alkyl, alkenyl oralkynyl moiety in a substituent group may be linear or branched.Examples of C₁-C₆ alkyl groups/moieties include methyl, ethyl, propyl,2-methyl-1-propyl, 2-methyl-2-propyl, 2-methyl-1-butyl,3-methyl-1-butyl, 2-methyl-3-butyl, 2,2-dimethyl-1-propyl,2-methyl-pentyl, 3-methyl-1-pentyl, 4-methyl-1-pentyl,2-methyl-2-pentyl, 3-methyl-2-pentyl, 4-methyl-2-pentyl,2,2-dimethyl-1-butyl, 3,3-dimethyl-1-butyl, 2-ethyl-1-butyl, n-butyl,isobutyl, tert-butyl, n-pentyl, isopentyl, neopentyl and n-hexyl.Examples of C₂-C₆ alkenyl groups/moieties include ethenyl, propenyl,1-butenyl, 2-butenyl, 1-pentenyl, 1-hexenyl, 1,3-butadienyl,1,3-pentadienyl, 1,4-pentadienyl and 1-hexadienyl. Examples of C₂-C₆alkynyl groups/moieties include ethynyl, propynyl, 1-butynyl, 2-butynyl,1-pentynyl and 1-hexynyl.

A C₁-C₆ haloalkyl or C₁-C₆ haloalkoxy substituent group/moiety willcomprise at least one halogen atom, e.g. one, two, three, four or fivehalogen atoms, examples of which include trifluoromethyl,trifluoromethoxy or pentafluoroethyl.

A C₁-C₆ hydroxyalkyl substituent group/moiety will comprise at least onehydroxyl group, e.g. one, two, three or four hydroxyl groups, examplesof which include —CH₂OH, —CH₂CH₂OH, —CH₂CH₂CH₂OH, —CH(OH)CH₂OH,—CH(CH₃)OH and —CH(CH₂OH)₂.

The alkyl groups in a di-C₁-C₆ alkylamino group/moiety may be the sameas, or different from, one another.

The ring A in formula (I) or (Ia) is a 5-membered heteroaromatic ringcontaining from 1 to 4 ring nitrogen atoms, examples of which includepyrrolyl, imidazolyl, pyrazolyl, triazolyl and tetrazolyl.

A heterocyclic ring system means a saturated, partially unsaturated orfully unsaturated hydrocarbyl group containing from 5 to 9 ring atoms inwhich one or more (e.g. one, two, three or four) ring carbon atoms arereplaced by a corresponding number of ring heteroatoms independentlyselected from nitrogen, oxygen and sulphur, particularly nitrogen andoxygen. Examples of heterocyclic ring systems include tetrahydrofuranyl,piperidinyl, pyrrolidinyl, tetrahydropyranyl, morpholinyl,thiamorpholinyl, dihydrobenzofuranyl, dihydrobenzothienyl and indolyl.

When any chemical moiety or group in formula (I) or (Ia) is described asbeing optionally substituted, it will be appreciated that the moiety orgroup may be either unsubstituted or substituted by one or more of thespecified substituents. It will be appreciated that the number andnature of substituents will be selected so as to avoid stericallyundesirable combinations.

In ring A of the compounds of formula (I), at least one of W, X, Y and Zrepresents N or NH. In one aspect of the invention, Y represents N or NHand W, X and Z each independently represent N, NH or CH. In a furtheraspect, Y represents N and W, X and Z each represent CH.

In one embodiment of the invention, at least two of W, X, Y and Zrepresent N or NH. Particularly advantageous compounds are those inwhich (i) X and Y each independently represent N or NH and W and Z bothrepresent CH, or (ii) Y and Z each independently represent N or NH and Wand X both represent CH, or (iii) W and X each independently represent Nor NH and Y and Z both represent CH.

In another embodiment, at least three of W, X, Y and Z independentlyrepresent N or NH.

Specific examples of ring A, in which m and R¹ are as previouslydefined, include:

Advantageously, the ring A (where the substituents R¹, which may be thesame or different, are as previously defined) is selected from thefollowing moieties:

In particular, the ring A may be selected from one of the followingmoieties:

The number (m) of substituents R¹ on ring A may be 0, 1, 2 or 3,preferably 2 or 3.

If present on ring A, each R¹ independently represents halogen (e.g.fluorine, chlorine or bromine), cyano, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy,C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl, C₁-C₆, or C₁-C₄, or C₁-C₂haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ haloalkoxy, C₁-C₆, or C₁-C₄, orC₁-C₂ alkylthio, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylcarbonyl, or C₁-C₆, orC₁-C₄, or C₁-C₂ alkyl optionally substituted by one or more (e.g. one,two, three or four) substituents independently selected from carboxyland C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl.

In an embodiment of the invention, each R¹ independently representshalogen (e.g. fluorine, chlorine or bromine), cyano, C₁-C₂ alkoxy, C₁-C₂alkoxycarbonyl, C₁-C₂ haloalkyl (e.g. difluoromethyl ortrifluoromethyl), C₁-C₂ haloalkoxy (e.g. difluoromethoxy ortrifluoromethoxy), C₁-C₂ alkylthio, C₁-C₂ alkylcarbonyl, or C₁-C₆, orC₁-C₄, or C₁-C₂ alkyl optionally substituted by one or more (e.g. one,two, three or four) substituents independently selected from carboxyland C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl.

In another embodiment, each R¹ independently represents halogen (e.g.fluorine, chlorine or bromine, especially chlorine), C₁-C₂ haloalkyl(e.g. difluoromethyl or trifluoromethyl) or C₁-C₆, or C₁-C₄, or C₁-C₂alkyl (especially methyl or ethyl).

The number (n) of substituents R² on the piperidine ring may be 0, 1, 2,3 or 4, and is preferably 0 or 1. A substituent R² may be attached atany suitable position on the piperidine ring but is preferably attachedat the 4-position relative to the ring nitrogen atom, i.e. thesubstituent R² is preferably attached to the same ring carbon atom asthe group R³.

If present, each R² independently represents halogen (e.g. fluorine,chlorine or bromine), cyano, carboxyl, hydroxyl, C₁-C₆, or C₁-C₄, orC₁-C₂ alkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, orC₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, or C₁-C₂ hydroxyalkyl, C₁-C₆, or C₁-C₄,or C₁-C₂ alkoxycarbonyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxyC₁-C₆ alkyl ora 5-, 6-, 7-, 8- or 9-membered heterocyclic ring system.

In one embodiment, each R² independently represents halogen (e.g.fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, C₁-C₂ alkyl(especially methyl), C₁-C₂ haloalkyl (e.g. difluoromethyl ortrifluoromethyl), C₁-C₂ alkoxy (especially methoxy), C₁-C₂ hydroxyalkyl(e.g. hydroxymethyl), C₁-C₂ alkoxycarbonyl (especially ethoxycarbonyl),C₁-C₂ alkoxyC₁-C₆ alkyl (preferably C₁-C₂ alkoxyC₁-C₂ alkyl) or a 5- to6-membered heterocyclic ring system containing one or two ringheteroatoms independently selected from nitrogen and oxygen.

In another embodiment, each R² independently represents halogen(especially fluorine), cyano, hydroxyl, C₁-C₂ alkyl (especially methyl),C₁-C₂ alkoxy (especially methoxy), C₁-C₂ alkoxycarbonyl (especiallyethoxycarbonyl), or C₁-C₂ alkoxyC₁-C₂ alkyl (particularlymethoxymethyl).

In still another embodiment, each R² independently represents cyano,hydroxyl, C₁-C₂ alkyl (especially methyl), C₁-C₂ alkoxy (especiallymethoxy), C₁-C₂ alkoxycarbonyl (especially ethoxycarbonyl), or C₁-C₂alkoxyC₁-C₂ alkyl (particularly methoxymethyl).

R³ represents an oxygen or sulphur atom, or a group C═O, NR⁵ or CR⁶R⁷where R⁵ represents a hydrogen atom or a C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl(preferably methyl) group and R⁶ and R⁷ each independently represent ahydrogen or halogen (e.g. fluorine, chlorine or bromine) atom, cyano,carboxyl, hydroxyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl, C₁-C₆, or C₁-C₄, orC₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, orC₁-C₂ hydroxyalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl, C₁-C₆, orC₁-C₄, or C₁-C₂ alkoxyC₁-C₆ alkyl or a 5-, 6-, 7-, 8- or 9-memberedheterocyclic ring system.

In one embodiment, R⁶ and R⁷ each independently represent a hydrogen orhalogen (e.g. fluorine, chlorine or bromine) atom, cyano, hydroxyl,C₁-C₂ alkyl (preferably methyl), C₁-C₂ haloalkyl (e.g. difluoromethyl ortrifluoromethyl), C₁-C₂ alkoxy, C₁-C₂ hydroxyalkyl (e.g. hydroxymethyl),or C₁-C₂ alkoxyC₁-C₂ alkyl (particularly methoxymethyl).

In one aspect of the invention, R³ represents an oxygen atom or a groupC═O, NR⁵ or CR⁶R⁷.

In another aspect, R³ represents an oxygen atom or a group NR⁵ or CR⁶R⁷.

In yet another aspect, R³ represents an oxygen atom or a group C═O, NH,N(CH₃), CH₂, CHF, CHCN, CH(OH), CH(OCH₃), CH(OC₂H₅), CH(CH₂OH),C(OH)CH₃, CH(CH₃), CH(CH₂OCH₃) or CH(CHF₂).

In a further aspect, R³ represents an oxygen atom or a group NH, N(CH₃),CH₂, CHF, CHCN, CH(OH), CH(OCH₃), CH(OC₂H₅), CH(CH₂OH), C(OH)CH₃,CH(CH₃), CH(CH₂OCH₃) or CH(CHF₂).

In a still further aspect, R³ represents an oxygen atom or a group C═O,NH, N(CH₃) or CH₂.

Compounds of formula (I) in which R³ is an oxygen atom are particularlypreferred.

R⁴ represents a 6-, 7-, 8-, 9- or 10-membered aromatic or heteroaromaticring system, the ring system itself being optionally substituted by atleast one substituent (e.g. one, two, three or four substituentsindependently) selected from halogen (e.g. fluorine, chlorine orbromine), hydroxyl, cyano, oxo (═O), C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl,C₂-C₆ or C₂-C₄ alkenyl, C₂-C₆ or C₂-C₄ alkynyl, C₁-C₆, or C₁-C₄, orC₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ hydroxyalkyl, C₁-C₆, orC₁-C₄, or C₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, or C₁-C₂ haloalkoxy, C₁-C₆, orC₁-C₄, or C₁-C₂ alkylthio, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylsulphinyl,C₁-C₆, or C₁-C₄, or C₁-C₂ alkylsulphonyl, C₁-C₆, or C₁-C₄, or C₁-C₂alkylcarbonyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylcarbonyloxy, C₁-C₆, orC₁-C₄, or C₁-C₂ alkoxycarbonyl, amino (—NH₂), —CON(R⁸)₂, C₁-C₆, orC₁-C₄, or C₁-C₂ alkylamino, di-(C₁-C₆ alkyl)amino, C₃-C₆ cycloalkyl,C₃-C₆ cycloalkyloxy and C₃-C₆ cycloalkylmethyl.

The heteroaromatic ring system will comprise at least one ringheteroatom (e.g. one, two, three or four ring heteroatoms independently)selected from nitrogen, sulphur and oxygen. Preferably the ringheteroatoms are selected from nitrogen and oxygen.

Examples of 6- to 10-membered aromatic or heteroaromatic ring systemsthat may be used, which may be monocyclic or polycyclic (e.g. bicyclic)in which the two or more rings are fused, include one or more (in anycombination) of phenyl, pyridinyl, naphthyl, benzofuranyl, benzothienyl,quinolinyl, imidazo[1,2-a]pyridinyl, pyrazinyl, indolyl, pyrimidinyl,thiophenyl and benzimidazolyl. Preferred ring systems include phenyl,naphthyl and pyridinyl.

In one embodiment of the invention, R⁴ represents a 6-, 7-, 8-, 9- or10-membered aromatic or heteroaromatic ring system, the ring systemitself being optionally substituted by at least one substituent (e.g.one, two, three or four substituents independently) selected fromhalogen (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, oxo,C₁-C₄ alkyl (e.g. methyl or ethyl), C₂-C₄ alkenyl (e.g. ethenyl), C₂-C₄alkynyl (e.g. ethynyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂hydroxyalkyl (e.g. hydroxymethyl), C₁-C₄ alkoxy (e.g. methoxy orethoxy), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy), C₁-C₄ alkylthio (e.g.methylthio or ethylthio), C₁-C₄ alkylsulphinyl (e.g. methylsulphinyl orethylsulphinyl), C₁-C₄ alkylsulphonyl (e.g. methylsulphonyl orethylsulphonyl), C₁-C₄ alkylcarbonyl (e.g. methylcarbonyl orethylcarbonyl), C₁-C₄ alkylcarbonyloxy (e.g. methylcarbonyloxy), C₁-C₄alkoxycarbonyl (e.g. methoxycarbonyl), amino, —CON(R⁸)₂, C₁-C₄alkylamino (e.g. methylamino or ethylamino), di-(C₁-C₄ alkyl)amino (e.g.dimethylamino), C₃-C₅ cycloalkyl, C₃-C₅ cycloalkyloxy and C₃-C₅cycloalkylmethyl.

In another embodiment of the invention, R⁴ represents a 6-, 7-, 8-, 9-or 10-membered, particularly 6-membered, aromatic or heteroaromatic(particularly a nitrogen-containing heteroaromatic) ring system, thering system itself being optionally substituted by at least onesubstituent (e.g. one, two, three or four substituents independently)selected from halogen (e.g. fluorine, chlorine or bromine), cyano, C₁-C₄alkyl (e.g. methyl or ethyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl),C₁-C₄ alkoxy (e.g. methoxy or ethoxy) and C₁-C₂ haloalkoxy (e.g.trifluoromethoxy).

In still another embodiment of the invention, R⁴ represents a 6-, 7-,8-, 9- or 10-membered, particularly 6-membered, aromatic orheteroaromatic (particularly a nitrogen-containing heteroaromatic) ringsystem, the ring system itself being optionally substituted by at leastone substituent (preferably up to three, most preferably one or two,substituents independently) selected from halogen (e.g. fluorine,chlorine or bromine), cyano, methyl, trifluoromethyl, methoxy andtrifluoromethoxy.

Each R⁸ independently represents a hydrogen atom or a C₁-C₆, or C₁-C₄,or C₁-C₂ alkyl, particularly methyl, group.

In the compounds of formula (Ia), the definitions of W¹, X¹, Y¹ and Z¹correspond respectively to the definitions of W, X, Y and Z in thecompounds of formula (I) as described above. Similarly the definitionsof p and q correspond respectively to the definitions of m and n in thecompounds of formula (I) as previously described.

If present on ring A, each R¹¹ independently represents halogen (e.g.fluorine, chlorine or bromine), cyano, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy,C₁-C₆, or C₁-C₄, or C₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂haloalkoxy, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylthio, C₁-C₆, or C₁-C₄, orC₁-C₂ alkylcarbonyl, or C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl optionallysubstituted by one or more (e.g. one, two, three or four) substituentsindependently selected from carboxyl and C₁-C₆, or C₁-C₄, or C₁-C₂alkoxycarbonyl.

In an embodiment of the invention, each R¹¹ independently representshalogen (e.g. fluorine, chlorine or bromine), cyano, C₁-C₂ alkoxy, C₁-C₂haloalkyl (e.g. difluoromethyl or trifluoromethyl), C₁-C₂ haloalkoxy(e.g. difluoromethoxy or trifluoromethoxy), C₁-C₂ alkylthio, C₁-C₂alkylcarbonyl, or C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl optionally substitutedby one or more (e.g. one, two, three or four) substituents independentlyselected from carboxyl and C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl.

In another embodiment, each R¹¹ independently represents halogen (e.g.fluorine, chlorine or bromine, especially chlorine), C₁-C₂ haloalkyl(e.g. difluoromethyl or trifluoromethyl) or C₁-C₆, or C₁-C₄, or C₁-C₂alkyl (especially methyl or ethyl).

The group R¹² in formula (Ia) corresponds to and has the same meaningsas the group R² in formula (I). Thus, if present, each R¹² independentlyrepresents halogen (e.g. fluorine, chlorine or bromine), cyano,carboxyl, hydroxyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl, C₁-C₆, or C₁-C₄, orC₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, orC₁-C₂ hydroxyalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl, C₁-C₆, orC₁-C₄, or C₁-C₂ alkoxyC₁-C₆ alkyl or a 5-, 6-, 7-, 8- or 9-memberedheterocyclic ring system.

In one embodiment, each R¹² independently represents halogen (e.g.fluorine, chlorine or bromine), cyano, carboxyl, hydroxyl, C₁-C₂ alkyl(especially methyl), C₁-C₂ haloalkyl (e.g. difluoromethyl ortrifluoromethyl), C₁-C₂ alkoxy (especially methoxy), C₁-C₂ hydroxyalkyl(e.g. hydroxymethyl), C₁-C₂ alkoxycarbonyl (especially ethoxycarbonyl),C₁-C₂ alkoxyC₁-C₆ alkyl (preferably C₁-C₂ alkoxyC₁-C₂ alkyl) or a 5- to6-membered heterocyclic ring system containing one or two ringheteroatoms independently selected from nitrogen and oxygen.

In another embodiment, each R¹² independently represents halogen(especially fluorine), cyano, hydroxyl, C₁-C₂ alkyl (especially methyl),C₁-C₂ alkoxy (especially methoxy), C₁-C₂ alkoxycarbonyl (especiallyethoxycarbonyl), or C₁-C₂ alkoxyC₁-C₂ alkyl (particularlymethoxymethyl).

In still another embodiment, each R¹² independently represents cyano,hydroxyl, C₁-C₂ alkyl (especially methyl), C₁-C₂ alkoxy (especiallymethoxy), C₁-C₂ alkoxycarbonyl (especially ethoxycarbonyl), or C₁-C₂alkoxyC₁-C₂ alkyl (particularly methoxymethyl).

R¹³ represents an oxygen atom, or a group C═O, NR¹⁵ or CR¹⁶R¹⁷, with theprovisos that (i) when R¹³ represents CO or NH and ring A representspyrazol-4-yl or imidazol-4-yl, then p must be 3 and R¹⁴ represents asubstituted (but not an unsubstituted) 6- to 10-membered aromatic orheteroaromatic ring system, and (ii) when R¹³ represents CH₂ and ring Arepresents pyrazol-4-yl or imidazol-4-yl, then either p is 3 or,alternatively, p is 2 and q is at least 1.

R¹⁵ represents a hydrogen atom or a C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl(preferably methyl) group and R¹⁶ and R¹⁷ each independently represent ahydrogen or halogen (e.g. fluorine, chlorine or bromine) atom, cyano,carboxyl, hydroxyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkyl, C₁-C₆, or C₁-C₄, orC₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, orC₁-C₂ hydroxyalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl, C₁-C₆, orC₁-C₄, or C₁-C₂ alkoxyC₁-C₆ alkyl or a 5-, 6-, 7-, 8- or 9-memberedheterocyclic ring system.

In one embodiment, R¹⁶ and R¹⁷ each independently represent a hydrogenor halogen (e.g. fluorine, chlorine or bromine) atom, cyano, hydroxyl,C₁-C₂ alkyl (preferably methyl), C₁-C₂ haloalkyl (e.g. difluoromethyl ortrifluoromethyl), C₁-C₂ alkoxy,

C₁-C₂ hydroxyalkyl (e.g. hydroxymethyl), or C₁-C₂ alkoxyC₁-C₂ alkyl(particularly methoxymethyl).

Subject to the above provisos, in one aspect, R¹³ represents an oxygenatom or a group NR¹⁵ or CR¹⁶R¹⁷. In a second aspect, R¹³ represents anoxygen atom or a group C═O, NH, N(CH₃), CH₂, CHF, CHCN, CH(OH),CH(OCH₃), CH(OC₂H₅), CH(CH₂OH), C(OH)CH₃, CH(CH₃), CH(CH₂OCH₃) orCH(CHF₂). In a third aspect, R¹³ represents an oxygen atom or a groupNH, N(CH₃), CH₂, CHF, CHCN, CH(OH), CH(OCH₃), CH(OC₂H₅), CH(CH₂OH),C(OH)CH₃, CH(CH₃), CH(CH₂OCH₃) or CH(CHF₂). In a fourth aspect, R¹³represents an oxygen atom. In a fifth aspect, R¹³ represents CH₂.

The group R¹⁴ in formula (Ia) corresponds to and has the same meaningsas the group R⁴ in formula (I).

Thus, R¹⁴ represents a 6-, 7-, 8-, 9- or 10-membered aromatic orheteroaromatic ring system, the ring system itself being optionallysubstituted by at least one substituent (e.g. one, two, three or foursubstituents independently) selected from halogen (e.g. fluorine,chlorine or bromine), hydroxyl, cyano, oxo (═O), C₁-C₆, or C₁-C₄, orC₁-C₂ alkyl, C₂-C₆ or C₂-C₄ alkenyl, C₂-C₆ or C₂-C₄ alkynyl, C₁-C₆, orC₁-C₄, or C₁-C₂ haloalkyl, C₁-C₆, or C₁-C₄, or C₁-C₂ hydroxyalkyl,C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxy, C₁-C₆, or C₁-C₄, or C₁-C₂ haloalkoxy,C₁-C₆, or C₁-C₄, or C₁-C₂ alkylthio, C₁-C₆, or C₁-C₄, or C₁-C₂alkylsulphinyl, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylsulphonyl, C₁-C₆, orC₁-C₄, or C₁-C₂ alkylcarbonyl, C₁-C₆, or C₁-C₄, or C₁-C₂alkylcarbonyloxy, C₁-C₆, or C₁-C₄, or C₁-C₂ alkoxycarbonyl, amino(—NH₂), —CON(R¹⁸)₂, C₁-C₆, or C₁-C₄, or C₁-C₂ alkylamino, di-(C₁-C₆alkyl)amino, C₃-C₆ cycloalkyl, C₃-C₆ cycloalkyloxy and C₃-C₆cycloalkylmethyl.

In one embodiment of the invention, R¹⁴ represents a 6-, 7-, 8-, 9- or10-membered aromatic or heteroaromatic ring system, the ring systemitself being optionally substituted by at least one substituent (e.g.one, two, three or four substituents independently) selected fromhalogen (e.g. fluorine, chlorine or bromine), hydroxyl, cyano, oxo,C₁-C₄ alkyl (e.g. methyl or ethyl), C₂-C₄ alkenyl (e.g. ethenyl), C₂-C₄alkynyl (e.g. ethynyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl), C₁-C₂hydroxyalkyl (e.g. hydroxymethyl), C₁-C₄ alkoxy (e.g. methoxy orethoxy), C₁-C₂ haloalkoxy (e.g. trifluoromethoxy), C₁-C₄ alkylthio (e.g.methylthio or ethylthio), C₁-C₄ alkylsulphinyl (e.g. methylsulphinyl orethylsulphinyl), C₁-C₄ alkylsulphonyl (e.g. methylsulphonyl orethylsulphonyl), C₁-C₄ alkylcarbonyl (e.g. methylcarbonyl orethylcarbonyl), C₁-C₄ alkylcarbonyloxy (e.g. methylcarbonyloxy), C₁-C₄alkoxycarbonyl (e.g. methoxycarbonyl), amino, —CON(R¹⁸)₂, C₁-C₄alkylamino (e.g. methylamino or ethylamino), di-(C₁-C₄ alkyl)amino (e.g.dimethylamino), C₃-C₅ cycloalkyl, C₃-C₅ cycloalkyloxy and C₃-C₅cycloalkylmethyl.

In another embodiment of the invention, R¹⁴ represents a 6-, 7-, 8-, 9-or 10-membered, particularly 6-membered, aromatic or heteroaromatic(particularly a nitrogen-containing heteroaromatic) ring system, thering system itself being optionally substituted by at least onesubstituent (e.g. one, two, three or four substituents independently)selected from halogen (e.g. fluorine, chlorine or bromine), cyano, C₁-C₄alkyl (e.g. methyl or ethyl), C₁-C₂ haloalkyl (e.g. trifluoromethyl),C₁-C₄ alkoxy (e.g. methoxy or ethoxy) and C₁-C₂ haloalkoxy (e.g.trifluoromethoxy).

In still another embodiment of the invention, R¹⁴ represents a 6-, 7-,8-, 9- or 10-membered, particularly 6-membered, aromatic orheteroaromatic (particularly a nitrogen-containing heteroaromatic) ringsystem, the ring system itself being optionally substituted by at leastone substituent (preferably up to three, most preferably one or two,substituents independently) selected from halogen (e.g. fluorine,chlorine or bromine), cyano, methyl, trifluoromethyl, methoxy andtrifluoromethoxy.

Each R¹⁸ independently represents a hydrogen atom or a C₁-C₆, or C₁-C₄,or C₁-C₂ alkyl, particularly methyl, group.

In a preferred embodiment of the invention, compounds of formula (I) arethose in which:

-   -   W, X, Y and Z each independently represent a nitrogen atom or a        moiety NH or CH, with the proviso that W, X, Y and Z do not each        simultaneously represent a moiety CH;    -   m is 2 or 3;    -   each R¹ independently represents halogen, C₁-C₆ haloalkyl or        C₁-C₆ alkyl;    -   n is 0 or 1;    -   R² represents cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, or C₁-C₆ alkoxyC₁-C₆ alkyl;    -   R³ represents an oxygen atom, or a group C═O, NR⁵ or CR⁶R⁷;    -   R⁵ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R⁶ and R⁷ each independently represent a hydrogen or halogen        atom or a cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ hydroxyalkyl or C₁-C₆ alkoxyC₁-C₆ alkyl group; and    -   R⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy.

In another preferred embodiment of the invention, compounds of formula(I) are those in which:

-   -   W, X, Y and Z each independently represent a nitrogen atom or a        moiety NH or CH, with the proviso that W, X, Y and Z do not each        simultaneously represent a moiety CH;    -   m is 2 or 3;    -   each R¹ independently represents halogen, C₁-C₆ haloalkyl or        C₁-C₆ alkyl;    -   n is 0 or 1;    -   R² represents cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆        alkoxycarbonyl, or C₁-C₆ alkoxyC₁-C₆ alkyl;    -   R³ represents an oxygen atom, or a group C═O, NR⁵ or CR⁶R⁷;    -   R⁵, R⁶ and R⁷ each independently represent a hydrogen atom or a        C₁-C₆ alkyl group; and    -   R⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy.

In a preferred embodiment of the invention, compounds of formula (Ia)are those in which:

-   -   W¹, X¹, Y¹ and Z¹ each independently represent a nitrogen atom        or a moiety NH or CH, with the proviso that W¹, X¹, Y¹ and Z¹ do        not each simultaneously represent a moiety CH;    -   p is 2 or 3;    -   each R¹¹ independently represents halogen, C₁-C₆ haloalkyl or        C₁-C₆ alkyl;    -   q is 0 or 1;    -   each R¹² represents cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        C₁-C₆ alkoxycarbonyl, or C₁-C₆ alkoxyC₁-C₆ alkyl;    -   R¹³ represents an oxygen atom or a group C═O, NR¹⁵ or CR₁₆R¹⁷,        with the provisos that (i) when R¹³ represents CO or NH and ring        A represents pyrazol-4-yl or imidazol-4-yl, then p must be 3 and        R¹⁴ represents a substituted 6- to 10-membered aromatic or        heteroaromatic ring system, and (ii) when R¹³ represents CH₂ and        ring A represents pyrazol-4-yl or imidazol-4-yl, then either p        is 3, or, p is 2 and q is at least 1;    -   R¹⁵, R¹⁶ and R¹⁷ each independently represent a hydrogen atom or        a C₁-C₆ alkyl group; and    -   R¹⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy; but        excluding compounds numbered 1) to 5), 7) to 9), 11) and 13)        to 25) as hereinbefore defined.

In another preferred embodiment of the invention, compounds of formula(Ia) are those in which:

-   -   W¹, X¹, Y¹ and Z¹ each independently represent a nitrogen atom        or a moiety NH or CH, with the proviso that W¹, X¹, Y¹ and Z¹ do        not each simultaneously represent a moiety CH;    -   p is 2 or 3;    -   each R¹¹ independently represents halogen, C₁-C₆ haloalkyl or        C₁-C₆ alkyl;    -   q is 0 or 1;    -   each R¹² represents cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,        C₁-C₆ alkoxycarbonyl, or C₁-C₆ alkoxyC₁-C₆ alkyl;    -   R¹³ represents an oxygen atom or a group C═O, NR¹⁵ or CR¹⁶R¹⁷,        with the provisos that (i) when R¹³ represents CO or NH and ring        A represents pyrazol-4-yl or imidazol-4-yl, then p must be 3 and        R¹⁴ represents a substituted 6- to 10-membered aromatic or        heteroaromatic ring system, and (ii) when R¹³ represents CH₂ and        ring A represents pyrazol-4-yl or imidazol-4-yl, then either p        is 3, or, p is 2 and q is at least 1;    -   R¹⁵ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁶ and R¹⁷ each independently represent a hydrogen or halogen        atom or a cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ hydroxyalkyl or C₁-C₆ alkoxyC₁-C₆ alkyl group; and    -   R¹⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy; but        excluding compounds numbered 1) to 5), 7) to 9), 11) and 13)        to 25) as hereinbefore defined.

In still another preferred embodiment of the invention, compounds offormula (Ia) are those in which:

-   -   W¹, X¹, Y¹ and Z¹ each independently represent a nitrogen atom        or a moiety NH or CH, with the proviso that W¹, X¹, Y¹ and Z¹ do        not each simultaneously represent a moiety CH;    -   p is 2 or 3;    -   each R¹¹ independently represents halogen, C₁-C₆ haloalkyl or        C₁-C₆ alkyl;

q is 0 or 1;

-   -   each R¹² represents cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ alkoxy,

C₁-C₆ alkoxycarbonyl, or C₁-C₆ alkoxyC₁-C₆ alkyl;

-   -   R¹³ represents an oxygen atom or a group NR¹⁵ or CR¹⁶R¹⁷, with        the provisos that (i) when R¹³ represents NH and ring A        represents pyrazol-4-yl or imidazol-4-yl, then p must be 3 and        R¹⁴ represents a substituted 6- to 10-membered aromatic or        heteroaromatic ring system, and (ii) when R¹³ represents CH₂ and        ring A represents pyrazol-4-yl or imidazol-4-yl, then either p        is 3, or, p is 2 and q is at least 1;    -   R¹⁵ represents a hydrogen atom or a C₁-C₆ alkyl group;    -   R¹⁶ and R¹⁷ each independently represent a hydrogen or halogen        atom or a cyano, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆        alkoxy, C₁-C₆ hydroxyalkyl or C₁-C₆ alkoxyC₁-C₆ alkyl group; and    -   R¹⁴ represents a 6- to 10-membered aromatic or heteroaromatic        ring system, the ring system itself being optionally substituted        by at least one substituent selected from halogen, cyano, C₁-C₆        alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆ haloalkoxy; but        excluding compounds numbered 1) to 5), 7), 9), 11), 13) to 23)        and 25) as hereinbefore defined.

Examples of novel compounds of formula (Ia) according to the inventioninclude:

-   4-(3,4-Dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(3,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-[4-(Trifluoromethoxy)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Methylphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(3-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-({1-[(1,3,5-Trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}oxy)benzonitrile,-   4-(4-Chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   1-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,-   1-{[1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-(4-methylphenoxyl)piperidine,-   1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,-   4-[4-(Trifluoromethyl)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(2,4-Dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Bromo-2-fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-chlorophenoxyl)piperidine,-   4-(4-Chlorophenoxy)-1-{[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,-   4-(3-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-Phenoxy-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Chlorophenoxy)-3-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(2,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(Naphthalen-2-yloxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(4-Chlorophenoxy)-2-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2,4-dichlorophenoxyl)piperidine,-   4-(2,4-Dichlorophenoxy)-1-{[1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,-   4-(2,4-Dichlorophenoxy)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(2,4-Dichlorophenoxy)-1-[(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidine,-   4-(2,4-Dichlorophenoxy)-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}piperidine,-   4-(4-Chloro-2-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   5-Chloro-2-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,-   1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine,-   1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(naphthalen-2-yloxy)piperidine,-   5-Chloro-2-{[1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,-   4-(4-Chloro-2-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(2,4-Dichlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,-   4-(4-Chlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,-   1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(2,6-dimethylphenoxyl)piperidine,-   4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(3-fluoro-4-methoxyphenoxy)piperidine,-   4-(3,5-Difluoro-4-methoxyphenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(3-Fluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(3,5-Difluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(4-Chloro-3-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(4-Chloro-2,6-difluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   4-(4-Chloro-3-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,-   5-Chloro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,-   (4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,-   (3,4-Dichlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,-   N-(4-Chlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,-   N-(3,4-Dichlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,-   4-Chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,-   3,4-Dichloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,-   4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(4-Chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(2,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(4-Chlorobenzyl)-4-(methoxymethyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   Ethyl    4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,-   Ethyl    4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,-   Ethyl    4-(4-bromobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,-   4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,-   4-(2,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,-   1-((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(4    chlorobenzyl)piperidine,-   4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(3,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(4-Chloro-3-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-methoxyphenoxy)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-methoxyphenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(2-fluorophenoxyl)piperidine,-   5-Chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,-   4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,-   4-(4-Chloro-2-fluorobenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   5-Chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,-   5-Chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-methoxypyridine,-   4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-methoxypiperidine,-   4-(4-Chloro-2-methoxybenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,-   4-(4-Chloro-2-methoxybenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   2-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,-   2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,-   (4-Chlorophenyl)(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,-   (4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,-   4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-((4-Chlorophenyl)(methoxy)methyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,-   1-(4-Chlorophenyl)-1-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,-   4-(1-(4-Chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-((4-Chlorophenyl)(ethoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,-   4-(1-(4-Chlorophenyl)-2-methoxyethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,-   1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(methoxy(phenyl)methyl)piperidine,-   4-(1-(4-Chlorophenyl)-2,2-difluoroethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,    and pharmaceutically acceptable salts of any one thereof.

It should be noted that each of the chemical compounds listed aboverepresents a particular and independent aspect of the invention.

Compounds of formula (I) and pharmaceutically acceptable salts thereofas defined above may be prepared by a process comprising

(i) reacting a compound of formula

wherein L¹ represents a leaving group (e.g. a halogen atom) and m, W, X,Y, Z and R¹ are as defined in formula (I), with a compound of formula

or a suitable salt (e.g. a hydrochloride salt) thereof, wherein n, R²,R³ and R⁴ are as defined in formula (I); or

(ii) reacting a compound of formula

wherein L² represents a leaving group (e.g. mesylate) and m, n, W, X, Y,Z, R¹ and R² are as defined in formula (I), with a compound of formulaL³-R³—R⁴ (V) wherein L³ represents a leaving group (e.g. mesylate) andR³ and R⁴ are as defined in formula (I);

and optionally thereafter carrying out one or more of the followingprocedures:

-   -   converting a compound of formula (I) into another compound of        formula (I)    -   removing any protecting groups    -   forming a pharmaceutically acceptable salt.

Process (i) above may conveniently be carried out in the presence of anorganic solvent such as dichloromethane, acetonitrile or tetrahydrofuranand a suitable base such as triethylamine, pyridine ordiisopropylethylamine, at a temperature in the range from 20° C. to 40°C., e.g. at ambient temperature (20° C.).

Process (ii) above may conveniently be carried out as for process (i)but at temperatures in the range from 20 to 80° C.

It will be appreciated that compounds of formula (Ia) may be prepared byprocesses analogous to those described above for the preparation ofcompounds of formula (I), that is, by a process comprising

(i) reacting a compound of formula

wherein L¹, p, W¹, X¹, Y¹, Z¹ and R¹¹ have the meanings defined above,with a compound of formula

or a suitable salt thereof, wherein q, R¹², R¹³ and R¹⁴ have themeanings defined above; or (ii) reacting a compound of formula

wherein L², p, q, W¹, X¹, Y¹, Z¹, R¹¹ and R¹² have the meanings definedabove, with a compound of formula L³-R¹³—R¹⁴ (Va) wherein L³, R¹³ andR¹⁴ have the meanings defined above.

Compounds of formula (II) in which L¹ represents a halogen atom may beprepared by reacting a compound of formula

wherein m, W, X, Y, Z and R¹ are as defined in formula (I), with sulphurdioxide in the present of an organometallic reagent (e.g. anorganolithium reagent such as n-butyl lithium), followed by reactionwith a halogenating agent, e.g. N-chlorosuccinimide.

The first step of the process is conveniently carried out in thepresence of an organic polar solvent such as ether, chloroform ordichloromethane under a nitrogen atmosphere at low temperature, e.g.from 0° C. to −70° C. The second step of the process may be carried outusing a biphasic solvent mixture, e.g. dichloromethane/water mixture, atambient temperature (20° C.).

Compounds of formula (IIa) may be prepared in an analogous manner to thecompounds of formula (II).

Compounds of formula (III) in which R³ represents an oxygen atom may beprepared by reacting a compound of formula

wherein P¹ represents a nitrogen-protecting group (e.g. tert-butoxycarbonyl group), R²⁰ represents a hydrogen atom or a leaving group (e.g.—SO₂Me) and n and R² are as defined in formula (I), with a compound offormula (VIII), HO—R⁴, wherein R⁴ is as defined in formula (I), in thepresence of a coupling agent (e.g. diisopropyl azodicarboxylate).

Compounds of formula (III) in which R³ represents a sulphur atom may beprepared as described in European Patent Application Publication No. EP1 227 090 (Kato et al).

Compounds of formula (III) in which R³ represents C═O may be prepared byprocesses analogous to those described by Orjales et al, J. Med. Chem.,2003, 46, 5512-5532 and Zhudu Tu et al, J. Med. Chem., 2009, 52,1358-1369.

Compounds of formula (III) in which R³ represents NR⁵ may be prepared asdescribed in International Patent Application Publication No. WO01/62757 (Hansen et al).

Compounds of formula (III) in which R³ represents CR⁶R⁷ may be preparedas described in European Patent Application Publication No. EP 1 227 090(Kato et al).

Compounds of formula (IIIa) may be prepared by processes analogous tothose used to prepare compounds of formula (III).

Compounds of formulae (IV), (IVa), (V), (Va), (VI), (VII) and (VIII) areeither commercially available, are well known in the literature or maybe prepared using known techniques.

It will be appreciated by those skilled in the art that in the aboveprocesses certain functional groups such as phenol, hydroxyl or aminogroups in the reagents may need to be protected by protecting groups.Thus, the preparation of compounds of formula (I) or (Ia) may involve,at an appropriate stage, the removal of one or more protecting groups.

The protection and deprotection of functional groups is described in‘Protective Groups in Organic Chemistry’, edited by J. W. F. McOmie,Plenum Press (1973) and ‘Protective Groups in Organic Synthesis’, 3^(rd)edition, T.W. Greene and P.G.M. Wuts, Wiley-Interscience (1999).

The compounds of formula (I) or (Ia) above may be converted to apharmaceutically acceptable salt thereof, preferably an acid additionsalt such as a hydrochloride, hydrobromide, benzenesulphonate(besylate), saccharin (e.g. monosaccharin), trifluoroacetate, sulphate,nitrate, phosphate, acetate, fumarate, maleate, tartrate, lactate,citrate, pyruvate, succinate, valerate, propanoate, butanoate, malonate,oxalate, 1-hydroxy-2-napthoate (xinafoate), methanesulphonate orp-toluenesulphonate salt.

In one aspect of the invention, compounds of formula (I) or (Ia) definedabove may bear one or more radiolabels. Such radiolabels may beintroduced by using radiolabel-containing reagents in the synthesis ofthe compounds of formula (I) or (Ia), or may be introduced by couplingthe compounds of formula (I) or (Ia) to chelating moieties capable ofbinding to a radioactive metal atom. Such radiolabeled versions of thecompounds may be used, for example, in diagnostic imaging studies.

Compounds of formula (I) or (Ia) and their salts may be in the form ofhydrates or solvates which form an aspect of the present invention. Suchsolvates may be formed with common organic solvents, including but notlimited to, alcoholic solvents e.g. methanol, ethanol or isopropanol.

Compounds of formula (I) or (Ia) above are capable of existing instereoisomeric forms. It will be understood that the inventionencompasses the use of all geometric and optical isomers (includingatropisomers) of the compounds of formula (I) or (Ia) and mixturesthereof including racemates. The use of tautomers and mixtures thereofalso form an aspect of the present invention. Enantiomerically pureforms are particularly desired.

The compounds of formula (I) or (Ia) and their pharmaceuticallyacceptable salts have activity as pharmaceuticals, in particular asprokineticin receptor modulators, and thus may be used in the treatmentof schizophrenia and other psychotic disorders (e.g., psychoticdisorder, psychosis), dementia and other cognitive disorders, anxietydisorders (e.g., generalized anxiety disorder), mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression), sleepdisorders, disorders usually first diagnosed in infancy, childhood, oradolescence (e.g., attention-deficit disorder and disruptive behaviourdisorders), pain (e.g. neuropathic pain), inflammatory conditions andneurodegenerative disorders (e.g. Parkinson's or Alzheimer's disease).

In the context of the present specification, the term “therapy” alsoincludes “prophylaxis” unless there are specific indications to thecontrary. The terms “therapeutic” and “therapeutically” should beconstrued accordingly.

Prophylaxis is expected to be particularly relevant to the treatment ofpersons who have suffered a previous episode of, or are otherwiseconsidered to be at increased risk of, the disorder or condition inquestion. Persons at risk of developing a particular disorder orcondition generally include those having a family history of thedisorder or condition, or those who have been identified by genetictesting or screening to be particularly susceptible to developing thedisorder or condition or those in the prodromal phase of a disorder.

In particular, the compounds of formula (I) or (Ia) and theirpharmaceutically acceptable salts as defined above may be used in thetreatment of the positive symptoms of schizophrenia, schizophreniformdisorder or schizoaffective disorder (e.g. voices or hallucinations),cognitive disorders (such as dementia and impaired learning) and alsopain (such as neuropathic pain).

The invention also provides a method of treating at least one symptom orcondition associated with schizophrenia, schizophreniform disorder,schizoaffective disorder and other psychotic disorders (e.g., psychoticdisorder, psychosis), dementia and other cognitive disorders, anxietydisorders (e.g., generalized anxiety disorder), mood disorders (e.g.,depressive disorders, major depressive disorders, bipolar disordersincluding bipolar I and II, bipolar mania, bipolar depression), sleepdisorders, disorders usually first diagnosed in infancy, childhood, oradolescence (e.g., attention-deficit disorder, autistic spectrumdisorders and disruptive behaviour disorders), pain (e.g. neuropathicpain) and neurodegenerative disorders (e.g. Parkinson's or Alzheimer'sdisease) which comprises administering to a patient in need thereof atherapeutically effective amount of a compound of formula (I) or (Ia) ora pharmaceutically acceptable salt thereof as hereinbefore defined.

Such symptoms and conditions include, but are not limited to, anxiety,agitation, hostility, panic, an eating disorder, an affective symptom, amood symptom, a negative and positive psychotic symptom commonlyassociated with psychosis and neurodegenerative disorder.

For the above-mentioned therapeutic uses the dosage administered will,of course, vary with the compound employed, the mode of administration,the treatment desired and the disorder indicated. For example, the dailydosage of a compound according to the invention (i.e. a compound offormula (I) or (Ia) or a pharmaceutically acceptable salt thereof), ifinhaled, may be in the range from 0.05 micrograms per kilogram bodyweight (μg/kg) to 100 micrograms per kilogram body weight (μg/kg).Alternatively, if the compound is administered orally, then the dailydosage of the compound of the invention may be in the range from 0.01micrograms per kilogram body weight (μg/kg) to 100 milligrams perkilogram body weight (mg/kg).

The compounds of formula (I) or (Ia) and pharmaceutically acceptablesalts thereof may be used on their own but will generally beadministered in the form of a pharmaceutical composition in which theformula (I) or (Ia) compound/salt (active ingredient) is in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier.

Therefore the present invention further provides a pharmaceuticalcomposition comprising a compound of formula (I) or (Ia) or apharmaceutically acceptable salt thereof as hereinbefore defined, inassociation with a pharmaceutically acceptable adjuvant, diluent orcarrier.

The invention still further provides a process for the preparation of apharmaceutical composition of the invention which comprises mixing acompound of formula (I) or (Ia) or a pharmaceutically acceptable saltthereof as hereinbefore defined with a pharmaceutically acceptableadjuvant, diluent or carrier.

Conventional procedures for the selection and preparation of suitablepharmaceutical formulations are described in, for example,“Pharmaceuticals—The Science of Dosage Form Designs”, M. E. Aulton,Churchill Livingstone, 1988.

Pharmaceutically acceptable adjuvants, diluents or carriers that may beused in the pharmaceutical compositions of the invention are thoseconventionally employed in the field of pharmaceutical formulation, andinclude, but are not limited to, sugars, sugar alcohols, starches, ionexchangers, alumina, aluminium stearate, lecithin, serum proteins, suchas human serum albumin, buffer substances such as phosphates, glycerine,sorbic acid, potassium sorbate, partial glyceride mixtures of saturatedvegetable fatty acids, water, salts or electrolytes, such as protaminesulphate, disodium hydrogen phosphate, potassium hydrogen phosphate,sodium chloride, zinc salts, colloidal silica, magnesium trisilicate,polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol,sodium carboxymethylcellulose, polyacrylates, waxes,polyethylene-polyoxypropylene-block polymers, polyethylene glycol andwool fat.

The pharmaceutical compositions of the present invention may beadministered orally, parenterally, by inhalation spray, rectally,nasally, buccally, vaginally or via an implanted reservoir. Oraladministration is preferred. The pharmaceutical compositions of theinvention may contain any conventional non-toxic pharmaceuticallyacceptable adjuvants, diluents or carriers. The term parenteral as usedherein includes subcutaneous, intracutaneous, intravenous,intramuscular, intra-articular, intrasynovial, intrasternal,intrathecal, intralesional and intracranial injection or infusiontechniques.

The pharmaceutical compositions may be in the form of a sterileinjectable preparation, for example, as a sterile injectable aqueous oroleaginous suspension. The suspension may be formulated according totechniques known in the art using suitable dispersing or wetting agents(such as, for example, Tween 80) and suspending agents. The sterileinjectable preparation may also be a sterile injectable solution orsuspension in a non-toxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablediluents and solvents that may be employed are mannitol, water, Ringer'ssolution and isotonic sodium chloride solution. In addition, sterile,fixed oils are conventionally employed as a solvent or suspendingmedium. For this purpose, any bland fixed oil may be employed includingsynthetic mono- or diglycerides. Fatty acids, such as oleic acid and itsglyceride derivatives are useful in the preparation of injectables, asare natural pharmaceutically acceptable oils, such as olive oil orcastor oil, especially in their polyoxyethylated versions. These oilsolutions or suspensions may also contain a long-chain alcohol diluentor dispersant such as that described in Ph. Helv. or a similar alcohol.

The pharmaceutical compositions of this invention may be orallyadministered in any orally acceptable dosage form including, but notlimited to, capsules, tablets, powders, granules, and aqueoussuspensions and solutions. These dosage forms are prepared according totechniques well-known in the art of pharmaceutical formulation. In thecase of tablets for oral use, carriers which are commonly used includelactose and corn starch. Lubricating agents, such as magnesium stearate,are also typically added. For oral administration in a capsule form,useful diluents include lactose and dried corn starch. When aqueoussuspensions are administered orally, the active ingredient is combinedwith emulsifying and suspending agents. If desired, certain sweeteningand/or flavouring and/or colouring agents may be added.

The pharmaceutical compositions of the invention may also beadministered in the form of suppositories for rectal administration.These compositions can be prepared by mixing the active ingredient witha suitable non-irritating excipient which is solid at room temperaturebut liquid at the rectal temperature and therefore will melt in therectum to release the active ingredient. Such materials include, but arenot limited to, cocoa butter, beeswax and polyethylene glycols.

The pharmaceutical compositions of this invention may be administered bynasal aerosol or inhalation. Such compositions are prepared according totechniques well-known in the art of pharmaceutical formulation and maybe prepared as solutions in saline, employing benzyl alcohol or othersuitable preservatives, absorption promoters to enhance bioavailability,fluorocarbons, and/or other solubilising or dispersing agents known inthe art.

Depending on the mode of administration, the pharmaceutical compositionwill preferably comprise from 0.05 to 99% w (per cent by weight), morepreferably from 0.05 to 80% w, still more preferably from 0.10 to 70% w,and even more preferably from 0.10 to 50% w, of active ingredient, allpercentages by weight being based on total composition.

The compounds of formula (I) or (Ia) and pharmaceutically acceptablesalts thereof as defined above may also be administered in conjunctionwith other compounds used for the treatment of the above conditions.

The invention therefore further relates to combination therapies whereina compound of formula (I) or (Ia) or a pharmaceutically acceptable saltthereof as previously defined or a pharmaceutical composition orformulation comprising a compound of formula (I) or (Ia) or apharmaceutically acceptable salt thereof as previously defined isadministered with another therapeutic agent or agents, for the treatmentof one or more of the conditions previously indicated. Such therapeuticagents may be selected from the following:

(i) antidepressants such as, for example, amitriptyline, amoxapine,bupropion, citalopram, clomipramine, desipramine, doxepin duloxetine,elzasonan, escitalopram, fluvoxamine, fluoxetine, gepirone, imipramine,ipsapirone, maprotiline, nortriptyline, nefazodone, paroxetine,phenelzine, protriptyline, reboxetine, robaizotan, sertraline,sibutramine, thionisoxetine, tranylcypromaine, trazodone, trimipramine,venlafaxine, and equivalents and pharmaceutically active isomer(s)and/or metabolite(s) thereof;

(ii) atypical antipsychotics including, for example, quetiapine andpharmaceutically active isomer(s) and/or metabolite(s) thereof;

(iii) antipsychotics including, for example, amisulpride, aripiprazole,asenapine, benzisoxidil, bifeprunox, carbamazepine, clozapine,chlorpromazine, debenzapine, divalproex, duloxetine, eszopiclone,haloperidol, iloperidone, lamotrigine, loxapine, mesoridazine,olanzapine, paliperidone, perlapine, perphenazine, phenothiazine,phenylbutlypiperidine, pimozide, prochlorperazine, risperidone,sertindole, sulpiride, suproclone, suriclone, thioridazine,trifluoperazine, trimetozine, valproate, valproic acid, zopiclone,zotepine, ziprasidone, and equivalents and pharmaceutically activeisomer(s) and/or metabolite(s) thereof;

(iv) anxiolytics including, for example, alnespirone, azapirones,benzodiazepines, barbiturates, and equivalents and pharmaceuticallyactive isomer(s) and/or metabolite(s) thereof. Example anxiolyticsinclude adinazolam, alprazolam, balezepam, bentazepam, bromazepam,brotizolam, buspirone, clonazepam, clorazepate, chlordiazepoxide,cyprazepam, diazepam, diphenhydramine, estazolam, fenobam,flunitrazepam, flurazepam, fosazepam, lorazepam, lormetazepam,meprobamate, midazolam, nitrazepam, oxazepam, prazepam, quazepam,reclazepam, tracazolate, trepipam, temazepam, triazolam, uldazepam, andzolazepam; and equivalents and pharmaceutically active isomer(s) and/ormetabolite(s) thereof;

(v) anticonvulsants including, for example, carbamazepine, valproate,lamotrogine, and gabapentin, and equivalents and pharmaceutically activeisomer(s) and/or metabolite(s) thereof;

(vi) Alzheimer's therapies including, for example, donepezil, memantine,tacrine, and equivalents and pharmaceutically active isomer(s) and/ormetabolite(s) thereof;

(vii) Parkinson's therapies including, for example, deprenyl, L-dopa,Requip, Mirapex, MAOB inhibitors such as selegine and rasagiline, comPinhibitors such as Tasmar, A-2 inhibitors, dopamine reuptake inhibitors,NMDA antagonists, Nicotine agonists, and Dopamine agonists andinhibitors of neuronal nitric oxide synthase, and equivalents andpharmaceutically active isomer(s) and/or metabolite(s) thereof;

(viii) migraine therapies including, for example, almotriptan,amantadine, bromocriptine, butalbital, cabergoline, dichloralphenazone,eletriptan, frovatriptan, lisuride, naratriptan, pergolide, pramipexole,rizatriptan, ropinirole, sumatriptan, zolmitriptan, and zomitriptan, andequivalents and pharmaceutically active isomer(s) and/or metabolite(s)thereof;

(ix) stroke therapies including, for example, abciximab, activase,NXY-059, citicoline, crobenetine, desmoteplase, repinotan, traxoprodil,and equivalents and pharmaceutically active isomer(s) and/ormetabolite(s) thereof;

(x) urinary incontinence therapies including, for example, darafenacin,falvoxate, oxybutynin, propiverine, robalzotan, solifenacin, andtolterodine, and equivalents and pharmaceutically active isomer(s)and/or metabolite(s) thereof;

(xi) neuropathic pain therapies including, for example, gabapentin,lidoderm, and pregablin, and equivalents and pharmaceutically activeisomer(s) and/or metabolite(s) thereof;

(xii) nociceptive pain therapies such as, for example, celecoxib,etoricoxib, lumiracoxib, rofecoxib, valdecoxib, diclofenac, loxoprofen,naproxen, and paracetamol, and equivalents and pharmaceutically activeisomer(s) and/or metabolite(s) thereof;

(xiii) insomnia therapies including, for example, allobarbital,alonimid, amobarbital, benzoctamine, butabarbital, capuride, chloral,cloperidone, clorethate, dexclamol, ethchlorvynol, etomidate,glutethimide, halazepam, hydroxyzine, mecloqualone, melatonin,mephobarbital, methaqualone, midaflur, nisobamate, pentobarbital,phenobarbital, propofol, roletamide, triclofos, secobarbital, zaleplon,and Zolpidem, and equivalents and pharmaceutically active isomer(s)and/or metabolite(s) thereof;

(xiv) mood stabilizers including, for example, carbamazepine,divalproex, gabapentin, lamotrigine, lithium, olanzapine, quetiapine,valproate, valproic acid, and verapamil, and equivalents andpharmaceutically active isomer(s) and/or metabolite(s) thereof;

(xv) 5HT1B ligands such as, for example, compounds disclosed in WO99/05134 and WO 02/08212;

(xvi) mGluR2 agonists;

(xvii) alpha 7 nicotinic agonists such as, for example, compoundsdisclosed in WO 96/006098, WO 97/030998, WO 99/003859, WO 00/042044, WO01/029034, WO 01/60821, WO 01/36417, WO 02/096912, WO 03/087102, WO03/087103, WO 03/087104, WO 2004/016617, WO 2004/016616, and WO2004/019947;

(xviii) chemokine receptor CCR1 inhibitors; and

(xix) delta opioid agonists such as, for example, compounds disclosed inWO 97/23466 and WO 02/094794.

Such combination products employ the compound of formula (I) or (Ia) ora pharmaceutically acceptable salt thereof as previously defined withinthe dosage range described herein and the other pharmaceutically activeagent within approved dosage ranges and/or the dosage such as describedin the publication reference.

In a further aspect the present invention provides a combination (forexample for the treatment of schizophrenia, cognitive disorders or pain)of a compound of formula (I) or (Ia) or a pharmaceutically acceptablesalt thereof as hereinbefore defined and one or more agentsindependently selected from carbamazepine, olanzapine, quetiapine,verapamil, lamotrigine, oxcarbazepine, risperidone, aripiprazol,ziprasidone and lithium.

The invention also provides a pharmaceutical product comprising, incombination, a preparation of a first active ingredient which is acompound of formula (I) or (Ia) or a pharmaceutically acceptable saltthereof as hereinbefore defined, and a preparation of a second activeingredient which is carbamazepine, olanzapine, quetiapine, verapamil,lamotrigine, oxcarbazepine, risperidone, aripiprazol, ziprasidone orlithium, for simultaneous, sequential or separate use in therapy.

In another aspect, the invention provides a kit comprising a preparationof a first active ingredient which is a compound of formula (I) or (Ia)or a pharmaceutically acceptable salt thereof as hereinbefore defined,and a preparation of a second active ingredient which is carbamazepine,olanzapine, quetiapine, verapamil, lamotrigine, oxcarbazepine,risperidone, aripiprazol, ziprasidone or lithium, and instructions forthe simultaneous, sequential or separate administration of thepreparations to a patient in need thereof.

The present invention will now be further explained by reference to thefollowing illustrative examples.

The methods used for synthesis of the compounds of the invention areillustrated by the general schemes below and the preparative examplesthat follow. The starting materials and reagents used in preparing thesecompounds are available from commercial suppliers. These general schemesare merely illustrative of methods by which the compounds of thisinvention can be synthesised, and various modifications to these schemescan be made and will be suggested to one skilled in the art havingreferred to this disclosure.

Nuclear magnetic resonance (NMR) spectra were recorded at 400 MHz; thechemical shifts (δ) are reported in parts per million. Spectra wererecorded using a Bruker 400 Avance instrument fitted with a 5 mm BBFOprobe or DUL probe. Instrument control was by Bruker TopSpin 2.1software, unless stated otherwise.

Purity was assessed using UPLC with UV (photodiode array) detection overa wide range of wavelengths, normally 220-450 nm, using a Waters AcquityUPLC system equipped with Acquity UPLC BEH or HSS C18 columns (2.1 mmid×50 mm long) operated at 50 or 60° C. Mobile phases typicallyconsisted of acetonitrile or methanol mixed with water containing either0.05% formic acid or 0.025% ammonia. Mass spectra were recorded with aWaters SQD single quadrupole mass spectrometer using atmosphericpressure ionisation, unless stated otherwise.

Compounds were purified using normal phase chromatography on silica oralumina, or by reverse phase chromatographic methods, using Biotage orIsolute KPNH Cartridge, SCX cartridge and SCX-2 solid phase extractioncartridges.

Preparative HPLC was performed using an Agilent Technologies 1100 Seriessystem or a Waters autopurification LC/MS system typically using Waters19 mm id×100 mm long C18 columns such as XBridge or SunFire 5 μmmaterials at room temperature. Mobile phases typically consisted ofacetonitrile or methanol mixed with water containing either 0.1% formicacid or 0.1% ammonia, unless stated otherwise.

Room temperature in the following schemes means the temperature rangingfrom 20° C. to 25° C.

The following abbreviations are used in the Examples:

AcOH Acetic acid

BF₃OEt Boron trifluoride diethyl etherate

Boc tert-Butoxycarbonyl

nBuLi n-Butyllithium

CDCl₃ Deuterated chloroform

DCM Dichloromethane

DIPEA Diisopropylethylamine

DMF N,N-Dimethyl formamide

DMSO Dimethyl sulfoxide

d6-DMSO Deuterated dimethyl sulfoxide

e.e. Percentage enantiomeric excess

Et Ethyl

EtOAc Ethyl acetate

EtOH Ethanol

Et₃N Triethylamine

IPE Diisopropyl ether

LCMS Liquid chromatography mass spectrum

MS Mass spectrum

MeOAc Methyl acetate

Me Methyl

MeCN Acetonitrile

MeOD Deuterated methanol

MeOH Methanol

MW Microwave

NaOH Sodium hydroxide

NaBH(OAc)₃ Sodium triacetoxyborohydride

NBS N-bromosuccinimide

NMR Nuclear magnetic resonance

Ph Phenyl

PhNO₂ Nitrobenzene

r.t. Room temperature, typically 20 to 25° C.

TFA Trifluoroacetic acid

THF Tetrahydrofuran

TLC Thin layer chromatography

HMBC-HMQC Heteronuclear multiple bond correlationspectroscopy-Heteronuclear multiple quantum correlation spectroscopy

1. INTERMEDIATES Intermediate 1: 3,5-Diethyl-1-methyl-1H-pyrazole

Methylhydrazine (5.0 mL, 95.3 mmol) in ethanol (10 mL) was addeddrop-wise to a stirred solution of 3,5-heptanedione (11 g, 85.2 mmol) at5° C. then allowed to stir at room temperature for 2 hours. Acetic acid(2 mL) was added and the mixture refluxed for 1 hour then allowed tocool to room temperature. The solution was concentrated in vacuo to givethe title compound (12 g, 94%).

MS ES⁺: 139

Intermediate 2: 1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazole

Prepared as described for 3,5-diethyl-1-methyl-1H-pyrazole(Intermediate 1) from methylhydrazine and1,1,1-trifluoropentane-2,4-dione.

MS ES⁺: 165

Intermediate 3: 3,5-Dimethyl-1H-pyrazole-4-sulfonyl chloride

3,5-Dimethyl-1H-pyrazole (3.0 g, 1.0 eq) dissolved in chloroform (5 mL)was added drop-wise to a solution of chlorosulfonic acid (19.95 g, 5.5eq.) in chloroform (20 mL) under a nitrogen atmosphere at 0° C. withcontinuous stirring. The reaction was heated at 60° C. for 15 hoursunder continuous stirring. The reaction was cooled to room temperatureand thionyl chloride (4.0 g, 1.1 eq) was gradually added. The reactionwas heated at 60° C. for a further 2 hours. The reaction was cooled toroom temperature and added to a stirred mixture of dichloromethane (50mL) and ice cold water (70 mL). The organic layer was separated and theaqueous layer was extracted with dichloromethane (2×70 mL). The combinedorganic layer was dried over sodium sulfate and evaporated under vacuumto obtain the title compound, 3,5-dimethyl-1H-pyrazole-4-sulfonylchloride (2.0 g, 42%), as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.40 (s, 6H)

MS ES⁺: 195

Intermediate 4: 3,5-Diethyl-1-methyl-1H-pyrazole-4-sulfonyl chloride

Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) from 3,5-diethyl-1-methyl-1H-pyrazole (Intermediate 1).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.21-1.40 (m, 6H), 2.85 (m, 2H), 2.95 (m,2H), 3.80 (s, 3H).

Intermediate 5: 1,3-Dimethyl-1H-pyrazole-4-sulfonyl chloride

Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) from 1,3-dimethylpyrazole.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.48 (s, 3H), 3.91 (s, 3H), 7.92 (s,1H).

MS ES⁺: 195

Intermediate 6: 3-(Trifluoromethyl)-1,5-dimethyl-1H-pyrazole

Prepared as described for 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) from 1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole(Intermediate 2).

¹H NMR (400 MHz, CDCl₃) δ ppm 2.63 (s, 3H), 3.91 (s, 3H)

Intermediate 7: 1,4-Dimethyl-1H-pyrazole-5-sulfonyl chloride

Step (i):

A solution of 23% n-butyl lithium in hexane (17.3 mL, 1.2 eq) was addeddrop-wise to a solution of 1,4-dimethyl-1H-pyrazole (5 g, 1 eq.) in dryether (50 mL) at −65° C. under a nitrogen atmosphere. The temperature ofthe resulting suspension was raised to 0° C. temperature over 1 hour andthen cooled to −70° C. Excess sulfur dioxide was bubbled to the mixturefor 30 minutes, while maintaining the temperature below −65° C. Thesolution was stirred at −65° C. for 1 hour and was then allowed to warmto room temperature. The resulting precipitate was filtered, washed withether and dried to yield the lithium sulfinate salt of1,4-dimethyl-1H-pyrazole.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 2.03 (s, 3H) 3.87 (s, 3H) 6.94 (s, 1H)

Step (ii):

The lithium sulfinate salt of 1,4-dimethyl-1H-pyrazole from step (i) wasadded to a biphasic mixture of dichloromethane (50 mL) and ice coldwater (70 mL). N-chlorosuccinimide (6.23 g, 0.9 eq.) was addedportion-wise with vigorous stirring. The reaction mixture was stirredfurther for 30 minutes at 5° C. The organic layer was separated and theaqueous layer was extracted with dichloromethane (2×30 mL). The combinedorganic layer was dried over sodium sulfate and evaporated under vacuumto obtain the title compound, 1,4-dimethyl-1H-pyrazole-5-sulfonylchloride (5.5 g, 55%). The regio-selectivity was confirmed by HMBC-HMQCanalysis.

Intermediate 8:1-(1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one

To a solution of 4-piperidine hydrochloride (3.67 g, 23.9 mmol) indichloromethane (250 mL) was added magnesium sulfate (5 g) and thereaction was stirred at room temperature. After 15 minutes,1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride ((1.0 g, 4.79 mmol) andtriethylamine (2.42 g, 23.9 mmol) were added successively and stirredovernight at room temperature. The reaction was filtered, treated withwater (25 mL) and extracted into dichloromethane (3×20 mL). The combinedorganic layers were dried over sodium sulfate, filtered and concentratedunder reduced pressure to afford the desired product,1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (1.24 g, 95%).

MS ES⁺: 272

Intermediate 9:1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

Prepared as described for1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate8) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride (Intermediate 3)and piperidine-4-carbonitrile.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.88 (m, 2H) 1.89-2.05 (m, 2H)2.20-2.37 (m, 6H) 2.65-2.86 (m, 2H) 2.94 (tt, J=8.56, 4.07 Hz, 1H)3.06-3.23 (m, 2H) 13.10 (br. s., 1H)

MS ES⁺: 269

Intermediate 10: 4-(4-Chloro-3-fluorophenoxy)piperidine hydrochloride

Step (i):

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (500 mg,2.484 mmol) and 4-chloro-3-fluorophenol in THF at 0° C. was treated withdiisopropyl azodicarboxylate (483 μl, 2.484 mmol). The reaction mixturewas stirred at room temperature for 40 hours. The reaction mixture wastreated with ethyl acetate and saturated aqueous sodium hydrogencarbonate. The layers were separated. The aqueous phase was extractedwith ethyl acetate and the organic layers were combined, dried overmagnesium sulfate, filtered and concentrated in vacuo to yield an oil.The crude product was purified by silica chromatography (solvent system:20-100% ethyl acetate/petrol). The relevant fractions were combined andconcentrated and the resulting product carried through to the next step.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41 (s, 9H) 1.44-1.57 (m, 2H) 1.85-1.96(m, 2H) 3.10-3.22 (m, 2H) 3.60-3.70 (m, 2H) 4.55-4.64 (m, 1H) 6.83-6.90(m, 1H) 7.10-7.17 (m, 1H) 7.42-7.49 (m, 1H)

Step (ii):

A solution of the tert-butyl4-(4-chloro-3-fluorophenoxy)piperidine-1-carboxylate from step (i) in1,4-dioxane (10 mL) was treated with 4M hydrogen chloride in dioxane (2equivalents). The reaction mixture was stirred at room temperature for16 hours. The product was filtered and dried under vacuum to give thetitle compound which was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.76-1.91 (m, 2H) 2.05-2.15 (m, 2H)2.98-3.11 (m, 2H) 3.15-3.27 (m, 2H) 4.63-4.72 (m, 1H) 6.86-6.94 (m, 1H)7.13-7.24 (m, 1H) 7.44-7.53 (m, 1H) 8.93 (br. s., 2H)

MS ES⁺: 230

Intermediate 11: 4-(4-Chloro-2-fluorophenoxy)piperidine hydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 4-chloro-2-fluorophenol.

Intermediate 12: 5-Chloro-2-(piperidin-4-yloxy)benzonitrilehydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 5-chloro-2-hydroxybenzonitrile.

Intermediate 13: 4-(3-Fluoro-4-methoxyphenoxy)piperidine hydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 3-fluoro-4-methoxyphenol.

Intermediate 14: 4-(4-Chloro-2-(trifluoromethyl)phenoxy)piperidinehydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 4-chloro-2-(trifluoromethyl)phenol.

Intermediate 15: 4-(3,5-Difluoro-4-methoxyphenoxy)piperidinehydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 3,5-difluoro-4-methoxyphenol.

Intermediate 16: 4-(4-Chloro-2,6-difluorophenoxy)piperidinehydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 4-chloro-2,6-difluorophenol.

Intermediate 17: 4-(4-(Trifluoromethyl)phenoxy)piperidine hydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 4-(trifluoromethyl)phenol.

Intermediate 18: 5-Chloro-2-(piperidin-4-yloxy)pyridine hydrochloride

Step (i):

Mesyl chloride (0.542 ml, 6.96 mmol) was added dropwise to a solution oftert-butyl 4-hydroxypiperidine-1-carboxylate (1 g, 4.97 mmol) andtriethylamine (0.970 ml, 6.96 mmol) in dichloromethane (25 ml) undernitrogen in an ice bath. The resulting solution was stirred at roomtemperature for 1 hour. The solution was washed with water, dried (phaseseparator) and concentrated to give tert-butyl4-(methylsulfonyloxy)piperidine-1-carboxylate (1.80 g, 6.44 mmol, 130%yield), as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40 (s, 9H) 1.52-1.72 (m, 2H) 1.80-2.04(m, 2H) 3.11-3.20 (m, 2H) 3.20 (s, 3H) 3.51-3.67 (m, 2H) 4.76-4.89 (m,1H)

Step (ii):

Potassium carbonate (0.352 g, 2.55 mmol) was added to a solution oftert-butyl 4-(methylsulfonyloxy)piperidine-1-carboxylate from step (i)(0.453 g, 1.621 mmol) and 5-chloropyridin-2-ol (0.15 g, 1.158 mmol) inN,N-dimethylformamide (10 ml) in a sealed tube. The reaction was stirredat 75° C. overnight. The reaction was quenched with water and extractedwith DCM three times. The combined organics were washed with water,dried (phase separator) and concentrated. The crude product wasfreeze-dried to remove the remaining DMF. The crude product was purifiedby 10 g KP-silica Biotage SNAP cartridge eluted with 0-50% ethylacetate/petrol to give tert-butyl4-(5-chloropyridin-2-yloxy)piperidine-1-carboxylate (0.116 g, 0.371mmol, 32.0% yield).

¹H NMR (400 MHz, Dichloromethane-d₂) δ ppm 1.48 (s, 9H) 1.64-1.81 (m,2H) 1.90-2.03 (m, 2H) 3.19-3.35 (m, 2H) 3.70-3.85 (m, 2H) 5.13-5.25 (m,1H) 6.73 (s, 1H) 7.52-7.62 (m, 1H) 8.05-8.14 (m, 1H)

MS ES⁺: 257

Step (iii):

A solution of the tert-butyl4-(5-chloropyridin-2-yloxy)piperidine-1-carboxylate from step (ii) in1,4-dioxane (10 mL) was treated with 4M HCl in dioxane (2 equivalents).The reaction mixture was stirred at room temperature for 16 hours. Theproduct was filtered and dried under vacuum to give the title compoundwhich was used without further purification.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.80-1.95 (m, 2H) 2.07-2.23 (m, 2H)3.00-3.15 (m, 2H) 3.17-3.27 (m, 2H) 5.10-5.26 (m, 1H) 6.85-6.96 (m, 1H)7.78-7.90 (m, 1H) 8.15-8.27 (m, 1H) 8.77 (br. s., 2H)

Intermediate 19: 4-(4-Chlorophenoxy)-2-methylpiperidine hydrochloride

(i) tert-Butyl 4-hydroxy-2-methylpiperidine-1-carboxylate

To a solution of 1-Boc-2-methyl-4-piperidinone (1.0 g, 4.68 mmol) inmethanol (10 mL) at 0° C. was added sodium borohydride (265 mg, 7.03mmol) portionwise. The reaction was stirred under an atmosphere ofnitrogen at 0° C. for 1 hour. It was then allowed to reach roomtemperature and stirred for a further 2.5 hours. The reaction was deemedcomplete by its LC-MS analysis and quenched using saturated ammoniumchloride aqueous solution and the methanol removed under reducedpressure. The remaining aqueous layer was extracted usingdichloromethane (25 ml×3), the combined organic layers were dried oversodium sulphate, filtered and concentrated under reduced pressure toafford the desired product, tert-butyl4-hydroxy-2-methylpiperidine-1-carboxylate (1.0 g, 100%).

MS ES⁺: 216.4

(ii) tert-Butyl 4-(4-chlorophenoxy)-2-methylpiperidine-1-carboxylate

Prepared as described for tert-Butyl4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate (Intermediate 20step (ii) from tert-Butyl 4-hydroxy-2-methylpiperidine-1-carboxylate(Intermediate 19 step (i)).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.15 (d, 3H), 1.40 (s, 9H), 1.41-1.49 (m,1H), 1.59-1.68 (m, 1H), 1.88-1.94 (m, 1H), 1.98-2.08 (m, 1H), 2.82-2.94(m, 1H), 3.98-4.08 (m, 1H), 4.34-4.48 (m, 1H), 4.46-4.54 (m, 1H),6.73-6.78 (m, 2H), 7.13-7.18 (m, 2H).

MS: ES+ 326

(iii) 4-(4-Chlorophenoxy)-2-methylpiperidine hydrochloride

A solution of the tert-butyl4-(4-chlorophenoxy)-2-methylpiperidine-1-carboxylate from step (ii) in1,4-dioxane (10 mL) was treated with 4M hydrogen chloride in dioxane.The reaction mixture was stirred at room temperature for 16 hours. Theproduct was filtered and dried under vacuum to give the title compoundwhich was used without further purification.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.48 (d, 3H), 1.80-2.28 (m, 4H), 3.12-3.78(m, 3H), 4.59-4.62 (m, 1H), 6.73-6.78 (m, 2H), 7.18-7.22 (m, 2H), 9.42(br.s, 1H), 9.71 (br.s, 1H).

MS: ES+ 226

Intermediate 20: 4-(4-Chlorophenoxy)-3-methylpiperidine hydrochloride

(i) tert-Butyl 4-hydroxy-3-methylpiperidine-1-carboxylate

Sodium borohydride (0.265 g, 7.03 mmol) was added in several portions toa solution of (R,S)-tert-butyl-3-methyl-4-oxopiperidine-1-carboxylate(1.0 g, 4.68 mmol) in methanol (10 mL) at 0° C. The reaction mixture wasstirred at 0° C. for one hour, then warmed to room temperature andstirred for 2.5 hours. The reaction mixture was quenched with saturatedammonium chloride aqueous solution and concentrated under reducedpressure in order to remove the methanol. This was extracted withdichloromethane. The combined organic layers were dried over sodiumsulfate, filtered and concentrated to afford the desired product as acolourless oil (quantitative yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 0.87-0.94 (m, 3H), 1.33-1.88 (m, 3H), 1.38(s, 9H), 2.23-4.08 (m, 5H).

MS: ES+ 216

(ii) tert-Butyl 4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate

Diethyl azodicarboxylate (0.46 mL, 2.90 mmol) was added to a solution oftert-butyl-4-hydroxy-3-methylpiperidine-1-carboxylate from step (i)(0.50 g, 2.32 mmol), 4-chlorophenol (0.25 g, 2.32 mmol) andtriphenylphosphine (0.76 g, 2.90 mmol) in tetrahydrofuran (10 mL). Thereaction mixture was stirred at room temperature overnight.

LCMS analysis showed no reaction, so heated to 50° C. overnight thencooled to room temperature. Diethyl ether was added and washed withwater, 0.4 M sodium hydroxide solution, water and brine. The organicphase was dried over sodium sulfate, filtered and concentrated. Theresidue was purified via silica gel flash column chromatography usingpetroleum ether:ethyl acetate (97:3) as solvent system in order toafford the desired product as a colourless oil (138 mg, 18% yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 0.95 (d, 3H), 1.40 (s, 9H), 1.36-1.50 (m,1H), 1.76-1.86 (m, 1H), 1.90-2.0 (m, 1H), 2.59-2.81 (m, 1H), 2.89-3.06(m, 1H), 3.70-3.99 (m, 3H), 6.74-6.79 (m, 2H), 7.13-7.18 (m, 2H).

MS: ES+ 326

(iii) 4-(4-Chlorophenoxy)-3-methylpiperidine hydrochloride

A solution of hydrochloric acid (4M in 1,4-dioxane) (0.53 mL, 2.11 mmol)was added to a solution oftert-butyl-4-(4-chlorophenoxy)-3-methylpiperidine-1-carboxylate fromstep (ii) (138 mg, 0.42 mmol) in 1,4-dioxane (10 mL) and the mixture wasstirred at room temperature overnight. A further portion of hydrochloricacid (4M in 1,4-dioxane) (5 mL, 20.02 mmol) was added to the mixture andstirred for three hours. The reaction mixture was concentrated and wasazeotroped with dichloromethane twice in order to give the desiredproduct as a cream solid (quantitative yield).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.19 (d, 3H), 1.90-2.37 (m, 3H), 2.71-2.71(m, 1H), 2.98-3.10 (m, 1H), 3.35-3.50 (m, 2H), 3.93-4.02 (m, 1H),6.73-6.77 (m, 2H), 7.10-7.22 (m, 2H), 9.50 (br.s, 1H), 9.69 (br.s, 1H).

MS: ES⁺: 226

Intermediate 21: Ethyl 4-(4-chlorobenzyl)piperidine-4-carboxylatehydrochloride

1-tert-Butyl 4-ethyl 4-(4-chlorobenzyl)piperidine-1,4-dicarboxylate (1g, 2.62 mmol) was treated with 4 M HCl in dioxane (4 ml, 16.00 mmol) andstirred at room temperature for 18 hours. The reaction was evaporated todryness to leave a white solid (0.708 g) that was used withoutpurification.

MS ES+: 282

Intermediate 22: tert-Butyl4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate

Magnesium turnings (0.98 g, 0.04 mol) was added to anhydrous diethylether (25 mL) followed by addition of catalytic amount of iodine (0.05g). The reaction was stirred at reflux under nitrogen atmosphere. Asolution of 3,4-dichlorobenzyl chloride (4.0 g, 0.02 mol) in diethylether (10 mL) was added drop wise to the reaction mass at refluxedtemperature and the resulting mixture was refluxed for 1.5 hrs. In aseparate flask, N-Boc-4-piperidone (2.46 g, 0.012 mol) was dissolved inanhydrous diethyl ether (50 mL) and cooled to 0° C. under nitrogen. Theprepared Grignard reagent was added to the solution at 0° C. and theresulting mixture was stirred at room temperature for 2 hours. Thereaction was diluted with saturated aqueous ammonium chloride andextracted with ethyl acetate. The organic layers were washed with brine,dried over sodium sulfate and concentrated. The crude compound waspurified by silica column chromatography eluted with 0-15% ethylacetate/n-hexane to afford tert-Butyl4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (3.0 g, 41%yield).

Intermediate 23: 4-(3,4-Dichlorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate

Trifluoroacetic acid (15 mL) was added to a solution of tert-butyl4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate22, 3.0 g, 8.3 mmol) in DCM (30 mL) at 0° C. The reaction was stirred atroom temperature for 45 minutes then concentrated and azeotroped withDCM to afford 4-(3,4-Dichlorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate (2.0 g, 65% yield).

Intermediate 24: tert-Butyl4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate

A suspension of triphenylphosphine (2.347 g, 8.95 mmol) and4-(bromomethyl)-1-chloro-2-fluorobenzene (2 g, 8.95 mmol) in ether (25mL) was stirred at room temperature overnight. The suspension wasconcentrated to give (4-chloro-3-fluorobenzyl)triphenylphosphoniumbromide (quantitative) as a white solid that was used crude. Butyllithium (1.6 M in hexanes) (6.03 mL, 9.65 mmol) was added slowly to asuspension of (4-chloro-3-fluorobenzyl)triphenylphosphonium bromide(4.26 g, 8.77 mmol) in THF (40 mL) under inert atmosphere at 0° C. Theresulting suspension was stirred at 0° C. for 15 minutes, then warmed toroom temperature for 2 hours. tert-Butyl 4-oxopiperidine-1-carboxylate(1.922 g, 9.65 mmol) as a solution in THF (5 mL) was added and thesuspension was stirred at room temperature overnight. Petroleum etherwas added, the precipitate (O═PPh3) was filtered and the filtrateconcentrated. The crude product was purified by silica chromatographyeluted with 0-100% DCM/petroleum ether to give tert-butyl4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (2.03 g, 6.23mmol, 71% yield) as a colourless oil that solidified on standing.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.42 (s, 9H) 2.28-2.30 (m, 2H) 2.39-2.40(m, 2H) 3.27-3.34 (m, 2H) 3.36-3.47 (m, 2H) 6.35 (s, 1H) 7.06-7.13 (m,1H) 7.25-7.28 (m, 1H) 7.51-7.55 (m, 1H)

Intermediate 25: 4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride

A flask charged with tert-butyl4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (2.03 g, 6.23mmol, Intermediate 24) and platinum(IV)oxide (0.141 g, 0.623 mmol) wasevacuated and flushed with argon three times. The flask was evacuatedagain and ethanol (20 mL) and ethyl acetate (20 mL) were added then thesuspension stirred under an atmosphere of hydrogen for 2 hours. Thesuspension was filtered through diatomaceous earth and the filtrateconcentrated to give tert-butyl4-(4-chloro-3-fluorobenzyl)piperidine-1-carboxylate (2.01 g, 6.13 mmol,98% yield) as a yellow oil that was used without further purification.Hydrogen chloride (4M in dioxane) (3.05 mL, 12.20 mmol) was added to asolution of tert-butyl4-(4-chloro-3-fluorobenzyl)piperidine-1-carboxylate (2 g, 6.10 mmol) inMethanol (20 mL) and stirred overnight. The solution was concentratedand azeotroped with toluene to give4-(4-chloro-3-fluorobenzyl)piperidine hydrochloride (1.56 g, 5.91 mmol,97% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.28-1.44 (m, 2H) 1.60-1.73 (m, 2H)1.74-1.88 (m, 1H) 2.54-2.60 (m, 2H) 2.69-2.86 (m, 2H) 3.15-3.25 (m, 2H)7.05-7.12 (m, 1H) 7.24-7.32 (m, 1H) 7.46-7.54 (m, 1H) 8.80 (br. s., 1H)9.06 (br. s., 1H)

Intermediate 26: 4-(4-Chloro-2-methoxyphenoxy)piperidine hydrochloride

Prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) from 4-chloro-2-methoxyphenol.

MS: ES+ 242

Intermediate 27: tert-Butyl4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate

Prepared as described for tert-Butyl4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate22) from 4-chloro-2-fluoro benzyl bromide.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30-1.42 (m, 13H) 2.69 (s, 2H) 2.99(br, s., 2H) 3.59-3.67 (m, 2H) 4.52 (s, 1H) 7.20-7.23 (m, 1H) 7.31-7.36(m, 2H)

Intermediate 28: 4-(4-Chloro-2-fluorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate

Prepared as described for 4-(3,4-Dichlorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate (Intermediate 23) using tert-Butyl4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 27).

MS: ES+ 244

Intermediate 29: 5-Chloro-3-fluoro-2-(piperidin-4-yloxy)pyridinehydrochloride

A solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (0.5 g, 2.4mmol) in DMF (5 mL) was added to a suspension of sodium hydride (0.065g, 2.7 mmol) in DMF (3 mL) at room temperature and stirred for 30minutes. 5-Chloro-2,3-difluoropyridine (0.4 g, 2.7 mmol) was added at 0°C. and then heated at 60° C. for 4 hours. The reaction was poured intocold water and extracted with ethyl acetate. The combined organic layerwas washed with brine and then dried over sodium sulfate andconcentrated. The crude compound was purified by silica columnchromatography eluted with 0-20% ethyl acetate in hexane to yieldtert-butyl 4-(5-chloro-3-fluoropyridin-2-yloxy) piperidine-1-carboxylate(0.5 g, 60% yield). 12% HCl in dioxane (5 mL) was added to tert-butyl4-(5-chloro-3-fluoropyridin-2-yloxy)piperidine-1-carboxylate (0.5 g, 1.5mmol) in dioxane (2 mL) and stirred at room temperature for 2 hours. Thereaction was concentrated. The crude compound was purified bytrituration with diethyl ether (10×2 mL) to afford5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride (0.3 g,34% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.88-1.97 (m, 2H) 2.13-2.19 (m, 2H)3.09-3.14 (m, 2H) 3.21-3.24 (m, 2H) 5.27-5.31 (m, 1H) 8.06-8.09 (m, 2H)8.91-8.92 (m, 2H)

Intermediate 30: 4-(4-Chloro-2-methoxybenzyl)piperidine hydrochloride

Prepared as described for 4-(4-chloro-3-fluorobenzyl)piperidinehydrochloride (Intermediate 25) using4-chloro-1-(chloromethyl)-2-methoxybenzene.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.27-1.41 (m, 2H) 1.60-1.70 (m, 2H)1.70-1.84 (m, 1H) 2.48 (br. s., 1H) 2.72-2.83 (m, 2H) 3.16-3.24 (m, 2H)3.80 (s, 3H) 6.92-6.97 (m, 1H) 7.03-7.06 (m, 1H) 7.11-7.16 (m, 1H) 8.51(br. s, 1H) 8.79 (br. s, 1H)

Intermediate 31: 4-(4-Chloro-2-fluorobenzyl)-4-fluoropiperidinehydrochloride

A solution of tert-butyl4-(4-chloro-2-fluorobenzyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 27, 5 g, 0.014 mol) in dry DCM (50 mL) was added dropwiseat −70° C. to a stirred solution of diethylaminosulfurtrifluoride (2.81g, 0.017 mol) in dry dichloromethane (50 mL) under nitrogen. Afterstirring at −50° C. for 45 min the reaction was warmed to roomtemperature. The reaction was poured into a saturated aqueous solutionof sodium bicarbonate and extracted with dichloromethane. The organiclayer was dried over sodium sulfate and concentrated. The crude compoundwas purified by silica column chromatography eluted with 0-5% ethylacetate/n-hexane to yield tert-butyl4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1.7 g, 34%yield). HCl-dioxane (30 mL) was added dropwise to tert-butyl4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine-1-carboxylate (1.7 g,0.005 mol) in dioxane (10 mL) at 0° C. The resulting solution wasstirred at room temperature for 1 hour. The reaction was concentrated.The crude compound was purified by triturating in diethyl ether (20mL×3) to yield 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidinehydrochloride (1.2 g, 87% yield).

MS: ES+ 246

Intermediate 32: tert-Butyl4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate

(4-chloro-2-methoxyphenyl) methanol (10 g, 0.058 mol) was dissolved inDCM (100 mL) and thionyl chloride (20.75 g, 0.174 mol) was addeddropwise under nitrogen at room temperature. The reaction was refluxedfor 30 minutes. The reaction was poured into ice water (100 mL) andextracted with dichloromethane. The organic layer was dried over sodiumsulfate and concentrated. The crude compound was purified by silicacolumn chromatography eluted with 0-10% ethyl acetate/n-hexane to yield4-chloro-2-methoxy benzyl chloride (9.1 g, 82.42% yield). Magnesiumturnings (1.26 g, 0.052 mol) were added to anhydrous diethyl ether (20mL) followed by addition of catalytic iodine (0.005 g). The reaction wasstirred at reflux under nitrogen. A solution of 4-chloro-2-methoxybenzyl chloride (5.0 g, 0.026 mol) in diethyl ether (15 mL) was addeddrop wise to the reaction at refluxed temperature and resulting mixturewas refluxed for 1.5 hours. In another flask, tert-butyl4-oxopiperidine-1-carboxylate (3.14 g, 0.015 mol) was dissolved inanhydrous diethyl ether (50 mL) and cooled to 0° C. under nitrogen. Theprepared Grignard reagent was added to the solution at 0° C. and theresulting mixture was stirred at room temperature for 2 hours. Thereaction was diluted with saturated aqueous ammonium chloride andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The crude compound waspurified by silica column chromatography eluted with 0-15% ethylacetate/n-hexane to yield tert-butyl4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate (3.4 g,37% yield).

MS: ES+ 256 (M-100 (boc group))

Intermediate 33: 4-(4-Chloro-2-methoxybenzyl)-4-methoxypiperidinehydrochloride

Sodium hydride (60% in paraffin; 0.56 g, 0.014 mol) was suspended in THF(50 mL) and tert-butyl4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 32, 2.5 g, 0.007 mol,) was added in THF (20 mL) slowly atroom temperature. The reaction mixture was heated to 50° C. for 2 hoursand then cooled to room temperature. Hexamethylphosphoramide (6.3 g,0.035 mol) and methyl iodide (10 g, 0.07 mol) were added and thereaction was stirred at 50° C. overnight. The reaction was poured intosaturated aqueous sodium bisulfate solution and extracted with ethylacetate. The organic layer was washed with brine, dried over sodiumsulfate and concentrated. The crude compound was purified by silicacolumn chromatography eluted with 0-15% ethyl acetate/n-hexane to yieldtert-butyl4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine-1-carboxylate (1.7 g,66% yield). HCl-dioxane (30 mL) was added dropwise to tert-butyl4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine-1-carboxylate (1.7 g,0.0046 mol) in dioxane (10 mL) at 0° C. and the resulting solution wasstirred at room temperature for 1 hour. The reaction was concentratedunder vacuum. The crude compound was purified by triturating in diethylether (20 mL×3) to yield4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride (1.3 g,93% yield).

MS: ES+ 270

Intermediate 34: 4-(4-Chloro-2-methoxybenzyl)piperidin-4-olhydrochloride

HCl-dioxane (30 mL) was added dropwise to tert-butyl4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 32, 3.0 g, 0.008 mol) in dioxane (10 mL) at 0° C. and theresulting solution was stirred at room temperature for 1 hour. Thereaction was concentrated. The crude compound was purified bytriturating in diethyl ether (20 mL×3) to yield4-(4-chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride (2.1 g, 86%yield).

MS: ES+ 256

Intermediate 35: 4-(4-Chloro-2-methoxybenzyl)-4-fluoropiperidinehydrochloride

Prepared as described for 4-(4-Chloro-2-fluorobenzyl)-4-fluoropiperidinehydrochloride (Intermediate 31) using tert-butyl4-(4-chloro-2-methoxybenzyl)-4-hydroxypiperidine-1-carboxylate(Intermediate 32).

MS: ES+ 258

Intermediate 36: tert-Butyl4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate

A solution of 2-(4-chloro-2-fluorophenyl)acetonitrile (0.353 g, 2.082mmol) in DMF (5 mL) was cooled to 0-5° C., to this was added sodiumhydride (0.050 g, 2.082 mmol) and tert-butyl4-bromopiperidine-1-carboxylate (0.5 g, 1.893 mmol). The reaction wasstirred at room temperature for 3 hours. The mixture was quenched withice/water and partitioned between ethyl acetate and water. The phaseswere separated and the aqueous extracted with ethyl acetate. Thecombined organics were washed with water, dried (Na₂SO₄) andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluted with 0-50% ethyl acetate/petroleumether to afford tert-butyl4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate (0.5g, 75%).

Intermediate 37:2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride

tert-Butyl4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate(Intermediate 36, 0.5 g, 1.417 mmol) was dissolved in Dioxane (1 mL) andHCl 12% in dioxane (5.02 mL, 19.84 mmol) added. The reaction was stirredat room temperature for 4 hours then concentrated under reduced pressureand triturated with diethyl ether to give2-(4-chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride(0.3 g, 85%).

Intermediate 38: tert-Butyl4-((4-chlorophenyl)(cyano)methyl)piperidine-1-carboxylate

Prepared as described for tert-butyl4-((4-chloro-2-fluorophenyl)(cyano)methyl)piperidine-1-carboxylate(Intermediate 36) from 2-(4-chlorophenyl)acetonitrile.

MS: ES− 333

Intermediate 39: 2-(4-Chlorophenyl)-2-(piperidin-4-yl)acetonitrilehydrochloride

Prepared as described for2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride(Intermediate 37) using tert-butyl 4-((4-chlorophenyl)(cyano)methyl)piperidine-1-carboxylate (Intermediate 38).

Intermediate 40: tert-Butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate

Di-tert-butyl dicarbonate (0.923 g, 4.23 mmol) was added to a solutionof (4-chlorophenyl)(piperidin-4-yl)methanone hydrochloride (1 g, 3.84mmol) and triethylamine (1.179 mL, 8.46 mmol) in Methanol (20 mL) undernitrogen. The reaction was stirred at room temperature overnight. Thesuspension was concentrated in vacuo. The residue was taken up in ethylacetate and water and the phases separated. The organic was washed withbrine, dried (phase separator) and concentrated to give tert-butyl4-(4-chlorobenzoyl)piperidine-1-carboxylate (1.22 g, 3.77 mmol, 98%yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.46 (m, 11H) 1.72-1.81 (m, 2H)2.83-3.00 (m, 2H) 3.62 (s, 1H) 3.92-4.02 (m, 2H) 7.58-7.65 (m, 2H)7.98-8.04 (m, 2H)

Intermediate 41: tert-Butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate

Sodium borohydride (0.140 g, 3.71 mmol) was added to a suspension oftert-butyl 4-(4-chlorobenzoyl)piperidine-1-carboxylate (Intermediate 40,1 g, 3.09 mmol) in Methanol (15 mL) under nitrogen at 0° C. The reactionwas stirred at room temperature for 1.5 hours. The reaction was quenchedwith water and the methanol evaporated. The aqueous was extracted withethyl acetate and the combined organics washed with brine, dried (phaseseparator) and concentrated to give tert-butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate (1.01 g,3.10 mmol, 100% yield) as a colourless oil.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00-1.12 (m, 2H) 1.20 (s, 1H) 1.37 (s,9H) 1.51-1.64 (m, 1H) 1.66-1.74 (m, 1H) 2.53-2.69 (m, 2H) 3.83-4.00 (m,2H) 4.27-4.33 (m, 1H) 5.29-5.33 (m, 1H) 7.28-7.33 (m, 2H) 7.34-7.39 (m,2H)

Intermediate 42: (4-Chlorophenyl)(piperidin-4-yl)methanol hydrochloride

Hydrogen chloride (4M in dioxane, 0.614 mL, 2.455 mmol) was added to asolution of tert-butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(Intermediate 41, 0.4 g, 1.228 mmol) in Methanol (10 mL). The reactionwas stirred at room temperature overnight. The solution was concentratedand azeotroped with toluene to give(4-chlorophenyl)(piperidin-4-yl)methanol hydrochloride (0.305 g, 1.163mmol, 95% yield) as a cream solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.33-1.47 (m, 3H) 1.67-1.84 (m, 2H) 2.74(br. s., 2H) 3.15-3.27 (m, 2H) 4.33-4.38 (m, 1H) 5.49-5.53 (m, 1H)7.30-7.35 (m, 2H) 7.37-7.43 (m, 2H) 8.48 (br. s., 1H) 8.93 (br. s., 1H)

Intermediate 43: 4-((4-Chlorophenyl)(methoxy)methyl)piperidinehydrochloride

Sodium hydride (60% in mineral oil, 0.221 g, 5.52 mmol) was added to asolution of tert-butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(Intermediate 41, 0.6 g, 1.841 mmol) in THF (15 mL) under nitrogen at 0°C. The reaction was stirred at room temperature for 45 minutes. Thesuspension was cooled and methyl iodide (0.345 mL, 5.52 mmol) was addedand then stirred at room temperature overnight. The reaction wasquenched with methanol and concentrated in vacuo. The crude product waspurified by column chromatography on silica, eluted with 0-20% ethylacetate/petroleum ether to afford tert-butyl4-((4-chlorophenyl)(methoxy)methyl)piperidine-1-carboxylate (0.545 g,1.604 mmol, 87% yield) as a colourless oil. Hydrogen chloride (4M indioxane) (0.802 mL, 3.21 mmol) was added to a solution of tert-butyl4-((4-chlorophenyl)(methoxy)methyl)piperidine-1-carboxylate (0.545 g,1.604 mmol) in methanol (10 mL). The reaction was stirred at roomtemperature overnight. The solution was concentrated in vacuo andazeotroped with toluene to give4-((4-chlorophenyl)(methoxy)methyl)piperidine hydrochloride (0.480 g,1.738 mmol, 108% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.25-1.49 (m, 3H) 1.77-1.96 (m, 2H)2.66-2.83 (m, 2H) 3.12 (s, 3H) 3.14-3.29 (m, 2H) 3.98-4.03 (m, 1H)7.27-7.32 (m, 2H) 7.43-7.49 (m, 2H) 8.33-8.60 (m, 2H)

Intermediate 44: tert-Butyl4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate

tert-Butyl 4-((4-chlorophenyl)(cyano)methyl)piperidine-1-carboxylate(Intermediate 38, 4 g, 11.95 mmol) was dissolved in toluene (15 mL) andcooled to −28° C., to this was added Diisobutylaluminium hydride (3.40g, 23.89 mmol). The reaction was stirred at room temperature for 2hours. The reaction mixture was quenched with ammonium chloride solutionthen acidified with 6N HCl to pH 2. Organic layer extracted and dried(Na₂SO₄) and concentrated under reduced pressure. The crude product waspurified by column chromatography on silica, eluted with 0-50% ethylacetate/petroleum ether to afford tert-butyl4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate (2 g, 50%yield).

Intermediate 45: tert-Butyl4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate

tert-Butyl 4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate(Intermediate 44, 0.7 g, 2.072 mmol) was dissolved in MeOH (20 mL) andcooled to 0-5° C., to this was added sodium borohydride (0.157 g, 4.14mmol). The reaction was stirred at room temperature for 2 hours. Thereaction mixture was concentrated under reduced pressure and DCM added,followed by water. The aqueous layer was extracted with DCM. Organiclayer dried (Na₂SO₄), filtered and concentrated under reduced pressure.The crude product was purified by column chromatography on silica,eluted with 0-50% ethyl acetate/petroleum ether to afford tert-butyl4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (0.7 g,35%).

Intermediate 46: 4-((4-Chlorophenyl)(ethoxy)methyl)piperidinehydrochloride

Sodium hydride (60% in mineral oil, 0.074 g, 1.841 mmol) was added to asolution of tert-butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(Intermediate 41, 0.5 g, 1.535 mmol) in THF (15 mL) under nitrogen at 0°C. The reaction was stirred at room temperature for 1.5 hours.Iodoethane (0.370 mL, 4.60 mmol) was added and the suspension stirred atroom temperature overnight. An additional portion of iodoethane (0.370mL, 4.60 mmol) was added and stirred over the weekend. The reaction wasquenched with methanol and concentrated in vacuo. The crude product waspurified by column chromatography on silica, eluted with 0-20% ethylacetate/petroleum ether to afford tert-butyl4-((4-chlorophenyl)(ethoxy)methyl)piperidine-1-carboxylate (0.445 g,1.257 mmol, 82% yield) as a colourless oil. Hydrogen chloride (4M indioxane) (0.629 ml, 2.51 mmol) was added to a solution of tert-butyl4-((4-chlorophenyl)(ethoxy)methyl)piperidine-1-carboxylate (0.445 g,1.257 mmol) in Methanol (5 mL). The reaction was stirred at roomtemperature overnight. The solution was concentrated and azeotroped withtoluene to give 4-((4-chlorophenyl)(ethoxy)methyl)piperidinehydrochloride (0.394 g, 1.358 mmol, 108% yield) as a colourless gum.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.04-1.13 (m, 3H) 1.30-1.47 (m, 3H)1.73-1.97 (m, 2H) 2.30 (s, 1H) 2.65-2.83 (m, 2H) 3.12-3.28 (m, 3H)4.04-4.14 (m, 1H) 7.26-7.35 (m, 2H) 7.40-7.49 (m, 2H) 8.74 (br. s., 2H)

Intermediate 47: 4-((4-Chlorophenyl)fluoromethyl)piperidinehydrochloride

Diethylaminosulfurtrifluoride (0.405 mL, 3.07 mmol) was added to asolution of tert-butyl4-((4-chlorophenyl)(hydroxy)methyl)piperidine-1-carboxylate(Intermediate 41, 0.5 g, 1.535 mmol) in DCM (15 mL) under nitrogen at−78° C. The reaction was stirred at −78° C. for 10 minutes, then at roomtemperature for 1 hour. The reaction was quenched with saturated aqueoussodium hydrogen carbonate. The aqueous was extracted with DCM. Thecombined organics were dried (phase separator) and concentrated invacuo. The crude product was purified by column chromatography onsilica, eluted with 0-20% ethyl acetate/petroleum ether to affordtert-butyl 4-((4-chlorophenyl)fluoromethyl)piperidine-1-carboxylate(0.425 g, 1.296 mmol, 84% yield) as a white solid.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41-1.59 (m, 3H) 1.77-1.90 (m, 1H)2.04-2.20 (m, 1H) 2.71-2.89 (m, 2H) 3.18-3.30 (m, 2H) 5.33-5.52 (m, 1H)7.34-7.43 (m, 2H) 7.45-7.56 (m, 2H) 8.68 (br. s., 1H) 9.03 (br. s., 1H)

2. EXAMPLES Example 14-(3,4-Dichlorophenoxy)-1((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

4-(3,4-Dichlorophenoxyl)piperidine hydrochloride (143 mg, 0.508 mmol)(prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) using 3,4-dichlorophenol) andtriethylamine (144 μL, 1.16 mmol) in dichloromethane (10 mL) was treatedwith 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride (106 mg, 0.508mmol). The reaction was stirred for 2 hours at room temperature. Thecrude reaction was washed with 1N hydrochloric acid, filtered through aphase separation cartridge and concentrated in vacuo. The crude productwas purified by silica column chromatography eluting with petrol/ethylacetate to give the title compound. (160 mg, 76%)

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.75 (m, 2H) 2.00-2.15 (m, 2H) 2.30(s, 3H) 2.45 (s, 3H) 2.78-2.86 (m, 2H) 3.34-3.42 (m, 2H) 3.75 (s, 3H)4.45-4.54 (m, 1H) 6.95-6.98 (m, 1H) 7.28 (s, 1H) 7.24 (m, 1H)

MS ES⁺: 419.

Example 24-(3,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(3,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.75 (m, 2H) 1.98-2.05 (m, 2H) 2.30(s, 3H) 2.40 (s, 3H) 2.75-2.89 (m, 2H) 3.30-3.40 (m, 2H) 4.48-4.54 (m,1H) 6.98 (m, 1H) 7.28 (m 1H) 7.48 (m, 1H) 13.0 (s, 1H)

MS ES⁺: 404.

Example 34-[4-(Trifluoromethoxy)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-(trifluoromethoxy)phenoxy)piperidine hydrochloride (prepared asdescribed for 4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride(Intermediate 10) using 4-(trifluoromethoxy)phenol).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.65-1.75 (m, 2H) 2.00-2.12 (m, 2H) 2.30(s, 3H) 2.44 (s, 3H) 2.80-2.92 (m, 2H) 3.24-3.33 (m, 2H) 3.76 (s, 3H)4.45-4.52 (m, 1H) 6.98 (m, 1H) 7.05 (d, J=7.7 Hz 2H) 7.28 (d, J=7.7 Hz1H)

MS ES⁺: 434.

Example 44-(4-Methylphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(p-tolyloxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.57-1.72 (m, 2H) 1.91-2.04 (m, 2H) 2.21(s, 3H) 2.26 (s, 3H) 2.41 (s, 3H) 2.77-2.88 (m, 2H) 3.18-3.30 (m, 2H)3.73 (s, 3H) 4.31-4.42 (m, 1H) 6.77-6.86 (m, 2H) 6.99-7.11 (m, 2H)

MS ES⁺: 364.

Example 54-(4-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.73 (m, 2H) 1.94-2.05 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.77-2.86 (m, 2H) 3.23-3.31 (m, 2H) 3.73 (s, 3H)4.39-4.47 (m, 1H) 6.92-6.99 (m, 2H) 7.26-7.32 (m, 2H)

MS ES⁺: 384.

Example 64-(3-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3-chlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.72 (m, 2H) 2.02-2.18 (m, 2H) 2.28(s, 3H) 2.42 (s, 3H) 2.80-2.92 (m, 2H) 3.06-3.15 (m, 2H) 3.72 (s, 3H)4.40-4.54 (m, 1H) 6.92 (d, 1H) 7.02 (d, 1H) 7.10 (s, 1H) 7.28 (m, 1H)

MS ES⁺384.

Example 74-({1-[(1,3,5-Trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}oxy)benzonitrile

Prepared as described for4-(3,4-dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(piperidin-4-yloxy)benzonitrile hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.78 (m, 2H) 2.04-2.12 (m, 2H) 2.30(s, 3H) 2.45 (s, 3H) 2.80-2.89 (m, 2H) 3.30-3.42 (m, 2H) 3.75 (s 3H)4.58-4.60 (m, 1H) 7.12 (d, J=7.8 Hz 2H) 7.75 (d, J=7.8 Hz 2H)

MS ES⁺: 375.

Example 84-(4-Chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chlorophenoxyl)piperidine hydrochloride(prepared as described for 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10) using 4-chlorophenol).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.73 (m, 2H) 1.98-2.06 (m, 2H) 2.35(s, 3H) 2.54 (s, 3H) 2.80-2.88 (m, 2H) 3.28-3.35 (m, 2H) 4.42-4.50 (m,1H) 6.98 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

MS ES⁺: 370.

Example 91-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1-ethyl-3,5-dimethyl-1H-pyrazole-4-sulfonyl chlorideand 4-(p-tolyloxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.30 (t 3H) 1.60-1.71 (m, 2H) 1.95-2.05(m, 2H) 2.21 (s, 3H) 2.30 (s, 3H) 2.45 (s, 3H) 2.80-2.88 (m, 2H)3.25-3.30 (m, 2H) 4.05-4.10 (q, 1H) 4.36-4.40 (m, 2H) 6.80 (d, J=7.8 Hz2H) 7.07 (d, J=7.8 Hz 2H)

MS ES⁺: 378.

Example 101-{[1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-(4-methylphenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole(Intermediate 6) and 4-(p-tolyloxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.71 (m, 2H) 1.95-2.05 (m, 2H) 2.25(s, 3H) 2.52 (s, 3H) 2.95-3.04 (m, 2H) 3.33-3.40 (m, 2H) 3.90 (s, 3H)4.38-4.45 (m, 1H) 6.83 (d, J=7.8 Hz 2H) 7.07 (d, J=7.8 Hz 2H)

MS ES⁺: 418.

Example 111-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chlorideand 4-(p-tolyloxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.74 (m, 2H) 2.00-2.08 (m, 2H) 2.28(s, 3H) 2.42 (s, 3H) 2.80-2.88 (m, 2H) 3.28-3.35 (m, 2H) 3.74 (s, 3H)4.40-4.48 (m, 1H) 6.95 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

MS ES⁺: 384.

Example 124-[4-(Trifluoromethyl)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-trifluoromethyl)phenoxypiperidine hydrochloride (Intermediate 17).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.76 (m, 2H) 2.05-2.12 (m, 2H) 2.30(s, 3H) 2.45 (s, 3H) 2.81-2.90 (m, 2H) 3.25-3.35 (m, 2H) 3.72 (s, 3H)4.58-4.62 (m, 1H) 7.15 (d, J=7.8 Hz 2H) 7.64 (d, J=7.8 Hz 2H)

MS ES⁺: 418.

Example 134-(2,4-Dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.81 (m, 2H) 1.96-2.01 (m, 2H) 2.28(s, 3H) 2.42 (s, 3H) 2.95-3.01 (m, 2H) 3.09-3.18 (m, 2H) 3.72 (s, 3H)4.60-4.68 (m, 1H) 7.26 (d, 1H) 7.34 (m, 1H) 7.55 (s, 1H)

MS ES⁺: 418.

Example 144-(4-Bromo-2-fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-bromo-2-fluorophenoxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.68-1.78 (m, 2H) 1.95-2.08 (m, 2H) 2.28(s, 3H) 2.43 (s, 3H) 2.80-2.90 (m, 2H) 3.24-3.30 (m, 2H) 3.75 (s, 3H)4.45-4.50 (m, 1H) 7.20 (m, 1H) 7.30 (m, 1H) 7.85 (m, 1H)

MS ES⁺: 448.

Example 151-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-chlorophenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chlorideand 4-(4-chlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.70 (m, 2H) 1.95-2.06 (m, 2H) 2.35(s, 3H) 2.90-3.00 (m, 2H) 3.30-3.40 (m, 2H) 3.84 (s, 3H) 4.45-4.50 (m,1H) 6.95 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H)

MS ES⁺: 404.

Example 164-(4-Chlorophenoxy)-1-{[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole(Intermediate 6) and 4-(4-chlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.75 (m, 2H) 1.97-2.06 (m, 2H) 2.50(s, 3H) 2.95-3.04 (m, 2H) 3.30-3.40 (m, 2H) 3.90 (s, 3H) 4.45-4.50 (m,1H) 6.95 (d, J=7.8 Hz 2H) 7.32 (d, J=7.8 Hz 2H)

MS ES⁺: 438.

Example 174-(3-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3-methoxyphenoxyl)piperidine hydrochloride

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.72 (m, 2H) 1.95-2.05 (m, 2H) 2.28(s, 3H) 2.42 (s, 3H) 2.78-2.86 (m, 2H) 3.28-3.35 (m, 5H) 3.78 (s, 3H)4.40-4.50 (m, 1H) 6.46-6.53 (m, 3H) 7.15 (t, 1H)

MS ES⁺: 380.

Example 184-(4-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-methoxyphenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.60-1.70 (m, 2H) 1.95-2.00 (m, 2H) 2.28(s, 3H) 2.43 (s, 3H) 2.80-2.90 (m, 2H) 3.22-3.28 (m, 2H) 3.70-3.80 (m,6H) 4.28-4.32 (m, 1H) 6.85 (m, 4H)

MS ES⁺: 380.

Example 194-Phenoxy-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-phenoxypiperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.74 (m, 2H) 1.96-2.07 (m, 2H) 2.27(s, 3H) 2.42 (s, 3H) 2.76-2.89 (m, 2H) 3.22-3.30 (m, 2H) 3.73 (s, 3H)4.39-4.50 (m, 1H) 6.85-6.97 (m, 3H) 7.21-7.31 (m, 2H)

MS ES⁺: 350.

Example 204-(4-Fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-fluorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.72 (m, 2H) 1.94-2.04 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.76-2.88 (m, 2H) 3.22-3.29 (m, 2H) 3.73 (s, 3H)4.32-4.43 (m, 1H) 6.90-6.98 (m, 2H) 7.03-7.14 (m, 2H)

MS ES⁺: 368.

Example 214-(4-Chlorophenoxy)-3-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chlorophenoxy)-3-methylpiperidine hydrochloride (Intermediate 20).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.07 (d, J=6.78, 3H) 1.68-1.77 (m, 1H)2.03-2.15 (m, 2H) 2.39 (s, 3H) 2.47 (s, 3H) 2.55-2.59 (m, 1H) 2.80-2.86(m, 1H) 3.42-3.49 (m, 2H), 3.77 (s, 3H) 3.81-3.86 (m, 1H) 6.78 (d,J=9.03, 2H) 7.21 (d, J=9.03, 2H)

MS ES⁺: 398.

Example 224-(2,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.84 (m, 2H) 1.90-2.02 (m, 2H) 2.32(s, 6H) 2.96-3.04 (m, 2H) 3.08-3.18 (m, 2H) 4.59-4.66 (m, 1H) 7.25 (m,1H) 7.33 (m, 1H) 7.55 (s, 1H) 9.45 (br.s, 1H)

MS ES⁺: 404.

Example 234-(Naphthalen-2-yloxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(naphthalen-2-yloxy)piperidine hydrochloride.

¹H NMR (400 MHz, Dichloromethane-d₂) δ ppm 1.94-2.19 (m, 4H) 2.34-2.41(s, 3H) 2.46-2.52 (s, 3H) 3.12-3.35 (m, 4H) 3.71-3.81 (s, 3H) 4.60 (m,1H) 7.09-7.21 (m, 2H) 7.32-7.43 (m, 1H) 7.47 (t, J=7.07 Hz, 1H)7.68-7.85 (m, 3H)

MS ES⁺: 400.

Example 244-(4-Chlorophenoxy)-2-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chlorophenoxy)-2-methylpiperidine hydrochloride (Intermediate 19).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.31 (d, J=7.12 3H) 1.76-1.85 (m, 1H)1.91-2.02 (m, 3H) 2.45 (s, 3H) 2.36 (m, 3H) 3.39-3.56 (m, 2H) 3.74 (s,3H) 4.10-4.17 (m, 1H) 4.61-4.64 (m, 1H) 6.78 (d, J=9.00 2H) 7.23 (d,J=9.00 2H)

MS ES⁺: 398.

Example 251-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2,4-dichlorophenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chlorideand 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.84 (m, 2H) 1.95-2.05 (m, 2H) 2.38(s, 3H) 3.06-3.15 (m, 2H) 3.18-3.24 (m, 2H) 3.84 (s, 3H) 4.64-4.70 (m,1H) 7.26 (d, 1H) 7.36 (m, 1H) 7.58 (s, 1H)

MS ES⁺: 440.

Example 264-(2,4-Dichlorophenoxy)-1-{[1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3-(trifluoromethyl)-1,5-dimethyl-1H-pyrazole(Intermediate 6) and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.80 (m, 2H) 1.96-2.04 (m, 2H) 2.50(s, 3H) 3.07-3.13 (m, 2H) 3.20-3.28 (m, 2H) 3.90 (s, 3H) 4.60-4.68 (m,1H) 7.25 (d, J=7.8 Hz 1H) 7.46 (m, 1H) 7.58 (s, 1H)

MS ES⁺: 472.

Example 274-(2,4-Dichlorophenoxy)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 5) and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.84 (m, 2H) 1.94-2.02 (m, 2H) 2.30(s, 3H) 2.95-3.12 (m, 4H) 3.80 (s, 3H) 4.64-4.70 (m, 1H) 7.26 (d, J=7.8Hz 1H) 7.34 (m, 1H) 7.58 (s, 1H) 8.24 (s, 1H)

MS ES⁺: 404.

Example 284-(2,4-Dichlorophenoxy)-1-[(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-diethyl-1-methyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 4) and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.08-1.20 (m, 6H) 1.70-1.80 (m, 2H)1.90-2.00 (m, 2H) 2.70 (q, 2H) 2.86 (q, 2H) 2.96-3.02 (m, 2H) 3.10-3.18(m, 2H) 3.80 (s, 3H) 4.60-4.70 (m, 1H) 7.28 (d, J=7.8 Hz 1H) 7.34 (m,1H) 7.57 (s, 1H)

MS ES⁺: 446.

Example 294-(2,4-Dichlorophenoxy)-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1-(difluoromethyl)-3,5-dimethyl-1H-pyrazole-4-sulfonylchloride and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.67-1.86 (m, 2H) 1.87-2.09 (m, 2H) 2.34(s, 3H) 2.61 (s, 3H) 3.10 (m, 4H) 4.59-4.78 (m, 1H) 7.19-7.29 (m, 1H)7.31-7.39 (m, 1H) 7.55 (m, 1H) 7.69-8.10 (m, 1H)

MS ES⁺: 454.

Example 304-(4-Chloro-2-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-fluorophenoxy)piperidine hydrochloride (Intermediate 11).

¹H NMR (400 MHz, Chloroform-d) δ ppm 1.88-2.10 (m, 4H) 2.40 (s, 3H) 2.48(s, 3H) 3.09-3.32 (m, 4H) 3.72-3.84 (m, 3H) 4.28-4.42 (m, 1H) 6.82-6.96(m, 1H) 7.03 (dd, J=8.66, 1.63 Hz, 1H) 7.10 (dd, J=10.79, 2.51 Hz, 1H)

MS ES⁺: 402.

Example 315-Chloro-2-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and5-chloro-2-(piperidin-4-yloxy)benzonitrile hydrochloride (Intermediate12).

¹H NMR (400 MHz, Chloroform-d) δ ppm 2.02 (d, J=3.76 Hz, 4H) 2.38 (s,3H) 2.48 (s, 3H) 2.95-3.18 (m, 2H) 3.30-3.49 (m, 2H) 3.76 (s, 3H) 4.62(br. s., 1H) 6.90 (d, J=8.78 Hz, 1H) 7.36-7.61 (m, 2H)

MS ES⁺: 409.

Example 321-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-(trifluoromethoxy)phenoxy)piperidinehydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.72 (m, 2H) 1.98-2.08 (m, 2H)2.28-2.40 (m, 6H) 2.80-2.88 (m, 2H) 3.24-3.33 (m, 2H) 4.44-4.52 (m, 1H)7.05 (d, J=7.8 Hz 2H) 7.30 (d, J=7.8 Hz 2H) 13.01 (s, 1H)

MS ES⁺: 420.

Example 331-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(naphthalen-2-yloxy)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(naphthalen-2-yloxy)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.80 (m, 2H) 2.10-2.18 (m, 2H) 2.30(m, 3H) 2.40 (s, 3H) 2.85-2.92 (m, 4H) 4.58-4.68 (m, 1H) 7.12 (m, 1H)7.30-7.58 (m, 3H) 7.74-7.82 (m, 3H) 13.01 (s, 1H)

MS ES⁺: 386

Example 345-Chloro-2-{[1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 5-chloro-2-(piperidin-4-yloxy)benzonitrilehydrochloride (Intermediate 12).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.86 (m, 2H) 1.91-2.10 (m, 2H) 2.27(s, 3H) 2.37 (s, 3H) 2.84-3.03 (m, 2H) 3.12-3.27 (m, 2H) 4.61-4.81 (m,1H) 7.29-7.43 (m, 1H) 7.64-7.76 (m, 1H) 7.90 (s, 1H) 13.09 (br.s, 1H)

MS ES⁺: 395

Example 354-(4-Chloro-2-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-fluorophenoxy)piperidinehydrochloride (Intermediate 11).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.80 (m, 2H) 1.93-2.10 (m, 2H) 2.28(s, 3H) 2.37 (s, 3H) 2.77-2.92 (m, 2H) 3.16-3.27 (m, 2H) 4.40-4.56 (m,1H) 7.15-7.32 (m, 2H) 7.43 (s, 1H) 13.11 (br. s., 1H)

MS ES⁺: 388.

Example 364-(2,4-Dichlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride(Intermediate 7) and 4-(2,4-dichlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, chloroform-d) δ ppm 2.00 (s, 4H) 2.28 (s, 3H) 3.20-3.35(m, 2H) 3.37-3.50 (m, 2H) 4.08 (s, 3H) 4.49-4.59 (m, 1H) 6.80-6.90 (m,1H) 7.14-7.21 (m, 1H) 7.36 (s, 2H)

MS ES⁺: 404

Example 374-(4-Chlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,4-dimethyl-1H-pyrazole-5-sulfonyl chloride(Intermediate 7) and 4-(4-chlorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, chloroform-d) δ ppm 1.90-2.03 (m, 4H) 2.27 (s, 3H)3.25-3.38 (m, 4H) 4.08 (s, 3H) 4.41-4.48 (m, 1H) 6.78-6.82 (m, 2H)7.20-7.25 (m, 2H) 7.37 (s, 1H)

MS ES⁺: 370.

Example 381-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(2,6-dimethylphenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(2,6-dimethylphenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61-1.77 (m, 2H) 1.88-2.02 (m, 2H) 2.17(s, 6H) 2.23-2.39 (m, 6H) 2.54-2.66 (m, 2H) 3.41-3.53 (m, 2H) 3.81-3.93(m, 1H) 6.83-6.94 (m, 1H) 6.96-7.04 (m, 2H)

MS ES⁺: 364.

Example 394-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-(trifluoromethyl)phenoxy)piperidine hydrochloride(Intermediate 14).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.83 (m, 2H) 1.90-2.03 (m, 2H) 2.25(s, 3H) 2.40 (s, 3H) 2.91-3.09 (m, 4H) 3.72 (s, 3H) 4.71-4.81 (m, 1H)7.31-7.40 (m, 1H) 7.60-7.71 (m, 2H)

MS ES⁺: 452.

Example 404-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-(trifluoromethyl)phenoxy)piperidinehydrochloride (Intermediate 14).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.85 (m, 2H) 1.88-2.05 (m, 2H) 2.30(s, 6H) 2.91-3.13 (m, 4H) 4.68-4.85 (m, 1H) 7.32-7.40 (m, 1H) 7.59-7.70(m, 2H) 13.09 (br. s., 1H)

MS ES⁺: 438.

Example 411-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(3-fluoro-4-methoxyphenoxy)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(3-fluoro-4-methoxyphenoxy)piperidinehydrochloride (Intermediate 13).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.76 (m, 2H) 1.88-2.05 (m, 2H) 2.32(s, 6H) 2.70-2.90 (m, 2H) 3.17-3.31 (m, 2H) 3.76 (s, 3H) 4.35 (tt,J=7.91, 3.71 Hz, 1H) 6.62-6.77 (m, 1H) 6.90 (dd, J=13.26, 2.91 Hz, 1H)6.97-7.15 (m, 1H) 13.05 (br. s., 1H)

MS ES⁺: 384.

Example 424-(3,5-Difluoro-4-methoxyphenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(3,5-difluoro-4-methoxyphenoxy)piperidinehydrochloride (Intermediate 15).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.54-1.72 (m, 2H) 1.91-2.08 (m, 2H) 2.32(br. s., 6H) 2.71-2.86 (m, 2H) 3.24-3.31 (m, 2H) 3.80 (s, 3H) 4.28-4.53(m, 1H) 6.81 (d, J=10.74 Hz, 2H) 13.08 (br. s., 1H)

MS ES⁺: 402.

Example 434-(3-Fluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3-fluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate 13).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.73 (m, 2H) 1.88-2.04 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.73-2.88 (m, 2H) 3.14-3.30 (m, 2H) 3.75 (d,J=12.51 Hz, 6H) 4.34 (tt, J=7.99, 3.76 Hz, 1H) 6.65-6.76 (m, 1H) 6.90(dd, J=13.26, 2.91 Hz, 1H) 7.04 (t, J=9.47 Hz, 1H)

MS ES⁺: 398.

Example 444-(3,5-Difluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3,5-difluoro-4-methoxyphenoxy)piperidine hydrochloride (Intermediate15).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.74 (m, 2H) 1.90-2.05 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.70-2.85 (m, 2H) 3.29 (d, J=6.06 Hz, 2H) 3.73 (s,3H) 3.80 (s, 3H) 4.41 (tt, J=8.21, 3.85 Hz, 1H) 6.68-6.97 (m, 2H)

MS ES⁺: 416.

Example 454-(4-Chloro-3-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-3-fluorophenoxy)piperidine hydrochloride (Intermediate 10).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.59-1.73 (m, 2H) 1.95-2.07 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.71-2.90 (m, 2H) 3.29 (br. s., 2H) 3.63-3.81 (m,3H) 4.36-4.56 (m, 1H) 6.82 (ddd, J=8.97, 2.84, 1.07 Hz, 1H) 7.10 (dd,J=11.62, 2.78 Hz, 1H) 7.43 (t, J=8.91 Hz, 1H)

MS ES⁺: 402.

Example 464-(4-Chloro-2,6-difluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2,6-difluorophenoxy)piperidine hydrochloride (Intermediate16).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.82 (m, 2H) 1.88-2.03 (m, 2H) 2.25(s, 3H) 2.40 (s, 3H) 2.89 (ddd, J=11.53, 7.99, 3.47 Hz, 2H) 3.09-3.25(m, 2H) 3.72 (s, 3H) 4.23 (dt, J=7.26, 3.69 Hz, 1H) 7.31-7.53 (m, 2H)

MS ES⁺: 420.

Example 474-(4-Chloro-3-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-3-fluorophenoxy)piperidinehydrochloride (Intermediate 10).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.55-1.77 (m, 2H) 1.91-2.06 (m, 2H) 2.33(br. s., 6H) 2.70-2.93 (m, 2H) 3.22-3.31 (m, 2H) 4.47 (tt, J=8.16, 3.84Hz, 1H) 6.82 (ddd, J=8.97, 2.78, 1.01 Hz, 1H) 7.10 (dd, J=11.68, 2.84Hz, 1H) 7.43 (t, J=8.91 Hz, 1H) 13.08 (br. s., 1H)

MS ES⁺: 388

Example 485-Chloro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and5-chloro-2-(piperidin-4-yloxy)pyridine hydrochloride (Intermediate 18).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.80 (m, 2H) 1.99-2.12 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.75-2.92 (m, 2H) 3.19-3.29 (m, 2H) 3.72 (s, 3H)4.92-5.05 (m, 1H) 6.80-6.87 (m, 1H) 7.73-7.86 (m, 1H) 8.14-8.20 (m, 1H)

MS ES⁺: 385

Example 49(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and(4-chlorophenyl)(piperidin-4-yl)methanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.50-1.65 (m, 2H) 1.76-1.80 (m, 2H) 2.28(s, 3H) 2.43 (s, 3H) 2.48-2.54 (m, 2H) 3.45-3.52 (m, 1H) 3.58-3.62 (m,2H) 3.78 (s, 3H) 7.60 (d, J=7.8 Hz 2H) 7.98 (d, J=7.8 Hz 2H)

MS ES⁺: 396

Example 50(3,4-Dichlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and(3,4-dichlorophenyl)(piperidin-4-yl)methanone.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.5-1.62 (m, 2H) 1.85-1.92 (m, 2H) 2.28(s, 3H) 2.45 (s, 3H) 2.45-2.58 (m, 2H) 3.48-3.55 (m, 1H) 3.60-3.65 (m,2H) 3.74 (s, 3H) 7.8 (d, J=7.5 Hz 1H) 7.95 (d, J=7.5 Hz 1H) 8.20 (d, 1H)

MS ES⁺: 430

Example 51N-(4-Chlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride andN-(4-chlorophenyl)piperidin-4-amine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.58 (m, 2H) 1.92-2.00 (m, 2H) 2.30(s, 3H) 2.40 (s, 3H) 2.45-2.55 (m, 2H) 3.28-3.35 (m, 1H) 3.52-3.60 (m,2H) 3.72 (s, 3H) 6.30 (br, 1H) 7.90 (br, 2H) 7.25 (br, 2H)

MS ES⁺: 383

Example 52N-(3,4-Dichlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride andN-(3,4-dichlorophenyl)piperidin-4-amine.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.46-1.58 (m, 2H) 1.92-2.00 (m, 2H) 2.30(s, 3H) 2.40 (s, 3H) 2.45-2.55 (m, 2H) 3.28-3.35 (m, 1H) 3.52-3.60 (m,2H) 3.72 (s, 3H) 6.30 (br, 1H) 7.90 (br, 1H) 7.25 (br, 1H)

MS ES⁺: 417

Example 534-Chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline

A mixture of 4-chloroaniline (276 mg, 2.17 mmol),1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate8, 590 mg, 2.17 mmol), acetic acid (303 mg, 5.05 mmol) and sodiumtriacetoxyborohydride (670 mg, 3.16 mmol) in 1,2-dichloroethane (21 mL)was stirred at room temperature overnight. Formaldehyde (37% in water,350 mg, 4.33 mmol) and sodium triacetoxyborohydride (918 mg, 4.33 mmol)were added to the reaction mixture and this was then stirred overnightat room temperature. Dichloromethane (50 mL) was added. The reactionmixture was washed with water (3×25 mL) and the organic layer separated,dried over sodium sulfate, filtered and concentrated under reducedpressure. The crude product was purified by silica chromatography toafford the desired product,4-chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline(132 mg, 15%).

¹H NMR (400 MHz, CDCl₃) δ ppm 1.76-1.94 (m, 4H) 2.39 (s, 3H) 2.42-2.49(m, 2H) 2.47 (s, 3H) 2.74 (s, 3H) 3.45-3.53 (m, 2H) 3.77 (s, 3H)3.86-3.89 (m, 1H) 6.66 (d, J=9.13 2H) 7.15 (d, J=9.13 2H)

MS ES⁺: 397

Example 543,4-Dichloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline

Prepared as described for4-chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline(Example 53) from1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate8) and 3,4-dichloroaniline.

¹H NMR (400 MHz, CDCl₃) δ ppm 1.76-1.93 (m, 4H) 2.39 (s, 3H) 2.44-2.50(m, 2H) 2.48 (s, 3H) 2.74 (s, 3H) 3.45-3.51 (m, 2H) 3.77 (s, 3H)3.86-3.91 (m, 1H) 6.56 (dd, J=3.00, 9.06 1H) 6.77 (d, J=3.00, 1H) 7.21(d, J=8.99, 1H)

MS ES⁺: 431

Example 554-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chlorobenzyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.24 (m, 2H) 1.43-1.55 (m, 1H)1.56-1.66 (m, 2H) 2.20-2.26 (m, 5H) 2.37 (s, 3H) 2.48 (m, 2H) 3.49-3.59(m, 2H) 3.70 (s, 3H) 7.14-7.20 (m, 2H) 7.28-7.35 (m, 2H)

MS ES⁺: 382

Example 564-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3,4-dichlorobenzyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.26 (m, 2H) 1.47-1.56 (m, 1H)1.57-1.65 (m, 2H) 2.15-2.26 (m, 5H) 2.37 (s, 3H) 3.49-3.59 (m, 4H) 3.70(s, 3H) 7.13-7.18 (m, 1H) 7.43-7.47 (m, 1H) 7.49-7.54 (m, 1H)

MS ES⁺: 416

Example 574-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

To a flask charged with magnesium turnings (0.087 g, 3.6 mmol, 3.0 eq)was added anhydrous diethyl ether (15 mL) followed by addition ofcatalytic amount of iodine (0.005 g). The reaction was heated at refluxand then 4-chloro benzyl chloride (0.588 g, 3.6 mmol, 3.0 eq) was addeddropwise. The resulting mixture was refluxed for 1 hour to produceGrignard reagent.1-(1,3,5-Trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (0.33 g, 1.2mmol, 1.0 eq, Intermediate 8) was dissolved in THF (10 mL) and cooled to0° C. The Grignard reagent was added to above solution at 0° C. and theresulting mixture was stirred at room temperature for 2 hours. Thereaction was diluted with saturated aqueous solution of ammoniumchloride and extracted with ethyl acetate. The organic layer was washedwith brine, dried over sodium sulfate and concentrated. The crudeproduct was purified by column chromatography using 60-120 mesh sizeneutral silica. The compound was eluted in 0-2% methanol indichloromethane to yield4-(4-chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyl)piperidin-4-ol.(0.18 g, 37.26% yield).

¹H NMR (400 MHz, Chloroform-d) δ ppm 1.51-1.69 (m, 2H) 1.80 (td,J=13.20, 4.43 Hz, 2H) 2.38 (s, 3H) 2.46 (s, 3H) 2.60-2.86 (m, 4H) 3.57(d, J=11.60 Hz, 2H) 3.76 (s, 3H) 7.13 (d, J=7.32 Hz, 2H) 7.23-7.46 (m,2H)

MS ES⁺: 398

Example 584-(4-Chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Sodium hydride (60% in paraffin; 0.033 g, 0.85 mmol, 2.0 eq) wassuspended in THF (5 mL) and4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol(Example 57, 0.17 g, 0.42 mmol, 1.0 eq) was added in THF (10 mL) slowlyat room temperature. The reaction mixture was heated to 50° C. for 2hours and then cooled to room temperature. Hexamethylphosphoramide(0.383 g, 2.14 mmol, 5.0 eq) and methyl iodide (0.6 g, 4.28 mmol, 10.0eq) were added and the reaction was stirred at 50° C. overnight. Thereaction was poured into saturated aqueous sodium bisulfate solution andextracted with ethyl acetate. The organic layer was washed with brine,dried over sodium sulfate and concentrated. The crude product waspurified by column chromatography using 60-120 mesh size neutral silica.The compound was eluted in 0-2% methanol in dichloromethane to yield4-(4-chlorobenzyl)-4-methoxy-1-(1,3,5-trimethyl-1H-pyrazol-4-ylsulfonyl)piperidine(0.15 g, 85.71% yield).

¹H NMR (400 MHz, chloroform-d) δ ppm 1.62-1.69 (m, 2H) 1.70-1.85 (m, 2H)2.39 (s, 3H) 2.44 (s, 3H) 2.55-2.69 (m, 2H) 2.74 (s, 2H) 3.27 (s, 3H)3.43-3.60 (m, 2H) 3.77 (s, 3H) 7.02-7.14 (m, 2H) 7.23-7.28 (m, 2H)

MS ES⁺: 412

Example 594-(2,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol(Example 57) from1-(1,3,5-trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-one (Intermediate8) and 2,4-dichloro-1-(chloromethyl)benzene.

¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 1.49-1.57 (m, 2H) 1.74 (s, 2H)2.30 (s, 3H) 2.41 (s, 3H) 2.50-2.56 (m, 1H) 2.56-2.71 (m, 2H) 2.91 (s,2H) 3.36-3.53 (m, 2H) 3.71 (s, 3H) 7.22-7.40 (m, 2H) 7.49 (s, 1H)

MS ES⁺: 432

Example 604-(4-Chlorobenzyl)-4-(methoxymethyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(4-chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 58) from(4-(4-chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol.

¹H NMR (400 MHz, acetonitrile-d₃) δ ppm 1.44-1.62 (m, 4H) 2.31 (s, 3H)2.42 (s, 3H) 2.55-2.71 (m, 2H) 2.84-3.02 (m, 4H) 3.07-3.20 (m, 2H) 3.27(s, 3H) 3.72 (s, 3H) 7.12 (s, 2H) 7.23-7.36 (m, 2H)

MS ES⁺: 426

Example 61 Ethyl4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride andethyl 4-(4-chlorobenzyl)piperidine-4-carboxylate hydrochloride(Intermediate 21).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.00 (t J=7 Hz 3H) 1.53-1.62 (m, 2H)1.97-2.06 (m, 2H) 2.21 (s, 3H) 2.25-2.35 (m 2H) 2.38 (s 3H) 2.78 (s 2H)3.33 (s 3H) 3.45-3.50 (m, 2H) 3.95-4.0.6 (ABq, J=8 Hz 2H) 7.08 (d, J=7.8Hz 2H) 7.34 (d, J=7.8 Hz 2H)

MS ES⁺: 454

Example 62 Ethyl4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and ethyl 4-(4-bromobenzyl)piperidine-4-carboxylatehydrochloride (prepared as described for ethyl4-(4-chlorobenzyl)piperidine-4-carboxylate hydrochloride (Intermediate21) using 1-tert-butyl 4-ethyl4-(4-bromobenzyl)piperidine-1,4-dicarboxylate).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.91-1.09 (m, 3H) 1.46-1.68 (m, 2H)1.96-2.04 (m, 2H) 2.12-2.42 (m, 8H) 2.77 (s, 2H) 3.38-3.57 (m, 2H)3.86-4.14 (m, 2H) 6.83-7.16 (m, 2H) 7.34-7.59 (m, 2H) 13.02 (br. s., 1H)

MS ES⁺: 485

Example 63 Ethyl4-(4-bromobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate

Prepared as described for ethyl4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate(Example 62) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.05 (t, 3H) 1.55-1.63 (m, 2H) 1.99-2.05(m, 2H) 2.22 (s, 3H) 2.28-2.34 (m, 2H) 2.38 (s, 3H) 2.76 (s, 2H)3.46-3.52 (m, 2H) 3.72 (s, 3H) 4.00 (ABq, 2H) 6.95 (d, J=7.8 Hz 2H) 7.54(d, J=7.8 Hz 2H)

MS ES⁺: 499

Example 644-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

A solution of1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile(Intermediate 9) (100 mg, 0.373 mmol) at 0° C. in THF (5 ml) was treatedwith lithium bis(trimethylsilyl)amide (1M in THF) (0.783 ml, 0.783mmol). The reaction mixture was stirred at 0° C. for 1 hour.1-chloro-4-(chloromethyl)benzene (60 mg, 0.373 mmol) was added. Thereaction was stirred at room temperature for 16 hours. The reaction wastreated with 10% aqueous citric acid and DCM. The layers were separated.The aqueous phase was extracted with dichloromethane and the organiclayers combined, dried over magnesium sulphate, filtered andconcentrated in vacuo. The crude product was purified by preparativeLCMS (basic conditions) to give the title compound,4-(4-chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile(56 mg, 34%).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73 (td, J=12.95, 3.79 Hz, 2H)1.80-1.95 (m, 2H) 2.26 (s, 3H) 2.29-2.42 (m, 5H) 2.93 (s, 2H) 3.65 (d,J=12.13 Hz, 2H) 7.31 (d, J=8.34 Hz, 2H) 7.42 (d, J=8.46 Hz, 2H) 13.09(s, 1H)

MS ES⁺: 393

Example 654-(2,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile

Prepared as described for4-(4-chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile(Example 64) from1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile(Intermediate 9) and 2,4-dichloro-1-(chloromethyl)benzene.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.72-1.87 (m, 2H) 1.89-2.04 (m, 2H) 2.26(s, 3H) 2.30-2.46 (m, 5H) 3.11 (s, 2H) 3.67 (d, J=12.38 Hz, 2H)7.41-7.54 (m, 2H) 7.66 (d, J=1.77 Hz, 1H) 13.10 (s, 1H)

MS ES⁺: 428

Example 664-(4-Chlorobenzyl)-1-((3,5-diethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

A solution of 3,5-heptanedione (12.5 g, 97.5 mmol) in ethanol (50 mL)was treated dropwise with hydrazine hydrate (60%, 5.72 g, 107 mmol)whilst cooling in an ice bath. The reaction was stirred for 1.5 hours atroom temperature. The reaction was concentrated under reduced pressure.The reaction mixture was partitioned between DCM and brine, the aqueouslayer was extracted with DCM. The combined organic layers were dried(Na₂SO₄), filtered and concentrated under reduced pressure to afford3,5-diethyl-1H-pyrazole that was used crude. 3,5-diethyl-1H-pyrazole(6.0 g, 0.048 mol) was added dropwise to chlorosulfonic acid (30.9 g,17.7 mL, 0.265 mol) at 0° C. with stirring. The reaction was heated to80° C. for 30 minutes. The reaction was cooled and thionyl chloride(6.32 g, 3.8 mL, 53.1 mol) was added dropwise. The reaction was heatedto 65° C. for 4 hours. The reaction mixture was cooled to roomtemperature and carefully poured onto ice (100 g) with stirring. Theresultant solid was filtered and dried under vacuum to afford3,5-diethyl-1H-pyrazole-4-sulfonyl chloride as a brown solid (9.15 g,85% yield). The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-diethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chlorobenzyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.25 (m, 8H) 1.45-1.75 (m, 3H)2.20-2.28 (m, 2H) 2.45-2.55 (m, 2H) 2.68-2.80 (m, 4H) 3.52-3.61 (m, 2H)4.10 (br s, 1H) 7.15-7.25 (m, 2H) 7.28-7.32 (m, 2H)

MS: ES+ 396

Example 674-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chlorobenzyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO d₆) δ ppm 1.34-1.59 (m, 4H) 1.88 (m, 1H) 2.54-2.61(m, 2H) 2.77 (s, 6H) 2.91-3.01 (4H, m) 720-7.25 (m, 2H) 7.44-7.48 (m,2H) 11.28 (br s, 1H)

MS: ES+ 368

Example 68 1-((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(4chlorobenzyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 5-chloro-1,3-dimethyl-1H-pyrazole-4-sulfonyl chlorideand 4-(4-chlorobenzyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.32-1.46 (m, 2H) 1.48-1.59 (m, 2H) 1.88(m, 1H) 2.52-2.60 (m, 2H) 2.78 (s, 3H) 2.91-3.11 (4H, m) 3.95 (s, 3H)7.21-7.27 (m, 2H) 7.42-7.46 (m, 2H)

MS: ES+ 402

Example 694-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(3,4-dichlorobenzyl)piperidin-4-ol 2,2,2-trifluoroacetate(Intermediate 23).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.35-1.45 (m, 2H) 1.55-1.53 (m, 2H) 2.20(s, 3H) 2.45 (s, 3H) 3.30-3.40 (4H, m) 3.70 (s, 3H) 7.20-7.22 (m, 1H)7.45 (1H, s) 7.55-7.60 (m, 2H)

MS: ES+ 432

Example 704-(3,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(3,4-dichlorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate (Intermediate 23).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.44 (m, 2H) 1.53-1.56 (m, 2H) 2.27(s, 3H) 2.45 (s, 3H) 3.30-3.40 (4H, m) 7.20-7.22 (m, 1H) 7.45 (1H, s)7.55-7.60 (m, 2H) 11.05 (br s, 1H)

MS: ES+ 418

Example 714-(4-Chloro-3-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride(Intermediate 25).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.07-1.28 (m, 2H) 1.44-1.71 (m, 3H)2.10-2.41 (m, 7H) 3.27-3.37 (m, 3H) 3.45-3.60 (m, 2H) 6.98-7.08 (m, 1H)7.17-7.25 (m, 1H) 7.40-7.53 (m, 1H) 13.00 (br. s., 1H)

MS: ES+ 386

Example 724-(4-Chloro-3-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-Chloro-3-fluorobenzyl)piperidine hydrochloride (Intermediate 25).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.25 (m, 2H) 1.47-1.66 (m, 3H)2.16-2.26 (m, 5H) 2.37 (s, 3H) 3.28-3.31 (m, 2H) 3.49-3.58 (m, 2H)3.68-3.72 (m, 3H) 6.99-7.06 (m, 1H) 7.20-7.26 (m, 1H) 7.43-7.50 (m, 1H)

MS: ES+ 400

Example 734-(4-Chloro-2-methoxyphenoxy)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-methoxyphenoxy)piperidinehydrochloride (Intermediate 26).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.62-1.74 (m, 2H) 1.87-1.99 (m, 2H)2.22-2.41 (m, 6H) 2.83-2.94 (m, 2H) 3.15-3.25 (m, 2H) 3.71 (s, 3H)4.30-4.39 (m, 1H) 6.85-6.90 (m, 1H) 6.98-7.04 (m, 2H) 13.08 (br. s., 1H)

MS: ES+ 400

Example 744-(4-Chloro-2-methoxyphenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-methoxyphenoxy)piperidine hydrochloride (Intermediate 26).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.63-1.75 (m, 2H) 1.89-2.00 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.81-2.90 (m, 2H) 3.15-3.25 (m, 2H) 3.71 (s, 3H)3.74 (s, 3H) 4.30-4.38 (m, 1H) 6.85-6.92 (m, 1H) 6.99-7.04 (m, 2H)

MS: ES+ 414

Example 754-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-Chloro-2-fluorobenzyl)piperidin-4-ol2,2,2-trifluoroacetate (Intermediate 28).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.34-1.44 (m, 2H) 1.53-1.56 (m, 2H) 2.27(s, 2H) 2.75 (s, 6H) 3.30-3.40 (4H, m) 7.20-7.22 (m, 1H) 7.45 (1H, s)7.55-7.60 (m, 2H) 11.05 (br s, 1H)

MS: ES+ 402

Example 761-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(2-fluorophenoxyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(2-fluorophenoxyl)piperidine hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.64-1.77 (m, 2H) 1.95-2.06 (m, 2H) 2.28(br. s., 3H) 2.37 (br. s., 3H) 2.81-2.91 (m, 2H) 3.21-3.29 (m, 2H)4.42-4.50 (m, 1H) 6.91-6.98 (m, 1H) 7.06-7.12 (m, 1H) 7.15-7.24 (m, 2H)13.07 (br. s., 1H)

MS: ES+ 354

Example 775-Chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and5-chloro-3-fluoro-2-(piperidin-4-yloxy)pyridine hydrochloride(Intermediate 29).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.73-1.84 (m, 2H) 2.02-2.12 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.82-2.91 (m, 2H) 3.21-3.29 (m, 2H) 3.73 (s, 3H)5.04-5.12 (m, 1H) 8.00-8.06 (m, 2H)

MS: ES+ 403

Example 784-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)piperidinehydrochloride (Intermediate 30).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.26 (m, 2H) 1.43-1.54 (m, 1H)1.54-1.64 (m, 2H) 2.16-2.28 (m, 5H) 2.33 (br. s., 3H) 2.41-2.47 (m, 2H)3.49-3.56 (m, 2H) 3.77 (s, 3H) 6.86-6.93 (m, 1H) 6.97-7.01 (m, 1H)7.05-7.11 (m, 1H) 13.00 (s, 1H)

MS: ES+ 398

Example 794-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-methoxybenzyl)piperidine hydrochloride (Intermediate 30).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.25 (m, 2H) 1.42-1.53 (m, 1H)1.54-1.63 (m, 2H) 2.14-2.25 (m, 5H) 2.37 (s, 3H) 2.42-2.47 (m, 2H)3.47-3.56 (m, 2H) 3.69 (s, 3H) 3.77 (s, 3H) 6.86-6.94 (m, 1H) 6.98-7.02(m, 1H) 7.06-7.11 (m, 1H)

MS: ES+ 412

Example 804-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidinehydrochloride (Intermediate 31).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.69-1.89 (m, 4H) 2.18-2.38 (m, 6H)2.39-2.47 (m, 2H) 2.89-3.02 (m, 2H) 3.41-3.51 (m, 2H) 7.21-7.28 (m, 1H)7.29-7.35 (m, 1H) 7.36-7.43 (m, 1H) 13.06 (br. s., 1H)

MS: ES+ 404

Example 814-(4-Chloro-2-fluorobenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-fluorobenzyl)-4-fluoropiperidine hydrochloride(Intermediate 31).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.70-1.88 (m, 4H) 2.23 (s, 3H) 2.38 (s,3H) 2.39-2.47 (m, 2H) 2.91-3.01 (m, 2H) 3.41-3.50 (m, 2H) 3.70 (s, 3H)7.22-7.28 (m, 1H) 7.28-7.35 (m, 1H) 7.37-7.43 (m, 1H)

MS: ES+ 418

Example 824-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

tert-Butyl 4-(4-chloro-2-fluorobenzylidene)piperidine-1-carboxylate wasprepared as described for tert-butyl4-(4-chloro-3-fluorobenzylidene)piperidine-1-carboxylate (Intermediate24) using 4-(bromomethyl)-1-chloro-3-fluorobenzene. Triethylsilane(2.157 mL, 13.50 mmol) was added dropwise to a suspension of palladiumon carbon (10% wt, 287 mg, 0.270 mmol) and tert-butyl4-(4-chloro-2-fluorobenzylidene)piperidine-1-carboxylate (880 mg, 2.70mmol) in methanol (50 mL) under nitrogen at 0° C. The reaction wasstirred at room temperature for 15 minutes. The suspension was filteredthrough diatomaceous earth and the filtrate concentrated in vacuo toafford tert-butyl 4-(4-chloro-2-fluorobenzyl)piperidine-1-carboxylate asa colourless oil (quantitative). This was then taken up in methanol (25mL) and HCl (4 M solution in dioxane, 1.35 mL) was added and thereaction was stirred at room temperature overnight. The reaction wasconcentrated in vacuo and azeotroped with toluene to give4-(4-chloro-2-fluorobenzyl)piperidine hydrochloride (0.715 g, 2.71 mmol,100% yield) as a white solid.

The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-fluorobenzyl)piperidine hydrochloride(described above).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.13-1.29 (m, 2H) 1.44-1.57 (m, 1H)1.57-1.67 (m, 2H) 2.18-2.33 (m, 10H) 3.48-3.59 (m, 2H) 7.18-7.24 (m, 1H)7.25-7.32 (m, 1H) 7.32-7.37 (m, 1H) 13.01 (br. s, 1H)

MS: ES+ 386

Example 834-(4-Chloro-2-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 82) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.28 (m, 2H) 1.43-1.55 (m, 1H)1.57-1.66 (m, 2H) 2.17-2.27 (m, 5H) 2.37 (s, 3H) 2.53-2.56 (m, 2H)3.50-3.58 (m, 2H) 3.69 (s, 3H) 7.18-7.23 (m, 1H) 7.25-7.32 (m, 1H)7.32-7.38 (m, 1H)

MS: ES+ 400

Example 845-Chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine

Sodium methoxide (0.053 g, 0.99 mmol) was added to a solution of5-chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine(Example 77, 0.2 g, 0.49 mmol) in methanol (1 mL) under nitrogen, thenheated to reflux for 5 hours. The reaction was concentrated and dilutedwith DCM and water. The phases were separated and the organic was dried(Na₂SO₄) and concentrated in vacuo. The crude product was purified bycolumn chromatography on silica, eluted with 0-70% ethyl acetate/hexaneto afford5-chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine(0.11 g, 55% yield).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.77 (m, 2H) 2.00-2.10 (m, 2H) 2.26(s, 3H) 2.41 (s, 3H) 2.75-2.83 (m, 2H) 3.26-3.33 (m, 2H) 3.73 (s, 3H)3.79 (s, 3H) 4.95-5.03 (m, 1H) 7.40-7.45 (m, 1H) 7.67-7.70 (m, 1H)

MS: ES+ 415

Example 855-Chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-methoxypyridine

Prepared as described for5-chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine(Example 84) from5-chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-fluoropyridine(prepared as described for5-chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine(Example 77) using 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3)).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.66-1.78 (m, 2H) 2.03 (br. s., 2H) 2.27(br. s., 3H) 2.37 (br. s., 3H) 2.79-2.89 (m, 2H) 3.23-3.31 (m, 2H) 3.78(s, 3H) 4.97-5.05 (m, 1H) 7.41-7.44 (m, 1H) 7.67-7.70 (m, 1H) 13.09 (br.s., 1H)

MS: ES+ 401

Example 864-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-methoxypiperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidinehydrochloride (Intermediate 33).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.48 (m, 2H) 1.67-1.75 (m, 2H) 2.29(s, 6H) 2.39-2.48 (m, 2H) 2.72 (s, 2H) 3.14 (s, 3H) 3.26-3.31 (m, 2H)3.78 (s, 3H) 6.91-6.95 (m, 1H) 7.01-7.03 (m, 1H) 7.07-7.12 (m, 1H) 13.01(br. s, 1H)

MS: ES+ 428

Example 874-(4-Chloro-2-methoxybenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-methoxybenzyl)-4-methoxypiperidine hydrochloride(Intermediate 33).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.48 (m, 2H) 1.67-1.75 (m, 2H) 2.22(s, 3H) 2.37 (s, 3H) 2.39-2.48 (m, 2H) 2.72 (s, 2H) 3.14 (s, 3H) 3.29(br. s., 2H) 3.71 (s, 3H) 3.78 (s, 3H) 6.90-6.96 (m, 1H) 7.00-7.05 (m,1H) 7.07-7.12 (m, 1H)

MS: ES+ 442

Example 884-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-methoxybenzyl)piperidin-4-ol hydrochloride (Intermediate34).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.40-1.53 (m, 4H) 2.22 (s, 3H) 2.37 (s,3H) 2.53-2.61 (m, 2H) 2.65 (s, 2H) 3.23-3.30 (m, 2H) 3.71 (s, 3H) 3.77(s, 3H) 4.29 (s, 1H) 6.89-6.94 (m, 1H) 6.99-7.02 (m, 1H) 7.13-7.18 (m,1H)

MS: ES+ 428

Example 894-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)piperidin-4-olhydrochloride (Intermediate 34).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.38-1.53 (m, 4H) 2.29 (s, 6H) 2.53-2.62(m, 2H) 2.65 (s, 2H) 3.21-3.30 (m, 2H) 3.77 (s, 3H) 4.29 (s, 1H)6.89-6.94 (m, 1H) 6.98-7.03 (m, 1H) 7.14-7.19 (m, 1H) 13.02 (br. s, 1H)

MS: ES+ 414

Example 904-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chloro-2-methoxybenzyl)-4-fluoropiperidinehydrochloride (Intermediate 35).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61-1.71 (m, 1H) 1.71-1.80 (m, 3H) 2.30(s, 6H) 2.53-2.58 (m, 2H) 2.86-2.95 (m, 2H) 3.37-3.46 (m, 2H) 3.80 (s,3H) 6.92-6.97 (m, 1H) 7.03-7.07 (m, 1H) 7.11-7.16 (m, 1H) 12.92-13.02(m, 1H)

MS: ES+ 416

Example 914-(4-Chloro-2-methoxybenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-(4-chloro-2-methoxybenzyl)-4-fluoropiperidine hydrochloride(Intermediate 35).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.61-1.70 (m, 1H) 1.70-1.79 (m, 3H) 2.23(s, 3H) 2.38 (s, 3H) 2.39-2.48 (m, 2H) 2.85-2.94 (m, 2H) 3.38-3.46 (m,2H) 3.71 (s, 3H) 3.79 (s, 3H) 6.93-6.98 (m, 1H) 7.04-7.09 (m, 1H)7.10-7.15 (m, 1H)

MS: ES+ 430

Example 922-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and2-(4-Chloro-2-fluorophenyl)-2-(piperidin-4-yl)acetonitrile hydrochloride(Intermediate 37).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.37-1.44 (m, 1H) 1.46-1.55 (m, 1H)1.83-1.91 (m, 1H) 2.20-2.28 (m, 5H) 2.33 (s, 5H) 3.53-3.60 (m, 1H)3.61-3.68 (m, 1H) 4.34-4.41 (m, 1H) 7.37-7.41 (m, 1H) 7.42-7.49 (m, 1H)7.54-7.59 (m, 1H) 13.05 (br. s., 1H)

MS: ES+ 411

Example 932-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 2-(4-chlorophenyl)-2-(piperidin-4-yl)acetonitrilehydrochloride (Intermediate 39).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.20-1.41 (m, 2H) 1.50-1.58 (m, 1H)1.75-1.92 (m, 2H) 2.17-2.33 (m, 8H) 3.53-3.68 (m, 2H) 4.20-4.27 (m, 1H)7.33-7.38 (m, 2H) 7.46-7.51 (m, 2H) 13.03 (br. s., 1H)

MS: ES+ 393

Example 94(4-Chlorophenyl)(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and (4-chlorophenyl)(piperidin-4-yl)methanolhydrochloride (Intermediate 42).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.14-1.36 (m, 3H) 1.36-1.51 (m, 1H)1.75-1.85 (m, 1H) 2.09-2.38 (m, 8H) 3.47-3.66 (m, 2H) 4.24-4.33 (m, 1H)5.27-5.36 (m, 1H) 7.23-7.31 (m, 2H) 7.32-7.42 (m, 2H) 13.00 (br. s., 1H)MS: ES+ 384

Example 95(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and(4-chlorophenyl)(piperidin-4-yl)methanol hydrochloride (Intermediate42).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.16-1.35 (m, 3H) 1.37-1.49 (m, 1H)1.74-1.84 (m, 1H) 2.09-2.19 (m, 2H) 2.21 (s, 3H) 2.36 (s, 3H) 3.48-3.63(m, 2H) 3.69 (s, 3H) 4.25-4.32 (m, 1H) 5.27-5.33 (m, 1H) 7.25-7.31 (m,2H) 7.33-7.39 (m, 2H)

MS: ES+ 398

Example 964-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-((4-chlorophenyl)(methoxy)methyl)piperidinehydrochloride (Intermediate 43).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H)1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H)3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

MS: ES+ 398

Example 974-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer A

4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 96) was separated into its enantiomers by supercritical fluidchromatography using a Daicel AD-H (250 mm×10 mm) column, eluting with14% MeOH to give4-((4-chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer A, as the first eluting peak.

e.e. 100%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H)1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H)3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

MS: ES+ 398

Example 984-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer B

4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 96) was separated into its enantiomers by supercritical fluidchromatography using a Daicel AD-H (250 mm×10 mm) column, eluting with14% MeOH to give4-((4-chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer B, as the second eluting peak.

e.e. 100%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.12-1.30 (m, 3H) 1.45-1.59 (m, 1H)1.90-1.98 (m, 1H) 2.08-2.37 (m, 8H) 3.07 (s, 3H) 3.46-3.65 (m, 2H)3.88-3.95 (m, 1H) 7.21-7.29 (m, 2H) 7.37-7.45 (m, 2H) 13.00 (br. s., 1H)

MS: ES+ 398

Example 994-((4-Chlorophenyl)(methoxy)methyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 1,3,5-trimethyl-1H-pyrazole-4-sulfonyl chloride and4-((4-chlorophenyl)(methoxy)methyl)piperidine hydrochloride(Intermediate 43).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.10-1.30 (m, 3H) 1.45-1.57 (m, 1H)1.86-1.98 (m, 1H) 2.07-2.18 (m, 1H) 2.19-2.23 (m, 4H) 2.36 (s, 3H) 3.07(s, 3H) 3.46-3.62 (m, 2H) 3.69 (s, 3H) 3.90-3.94 (m, 1H) 7.22-7.28 (m,2H) 7.38-7.44 (m, 2H)

MS: ES+ 412

Example 1002-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol

2-(4-Chlorophenyl)-2-(piperidin-4-yl)ethanol hydrochloride (Intermediate45, 0.7 g, 2.1 mmol) was dissolved in HCl (12% in dioxane, 3 mL) andstirred at room temperature for 4 hours. The reaction was concentratedin vacuo and the crude product was triturated with diethyl ether to give2-(4-chlorophenyl)-2-(piperidin-4-yl)ethanol hydrochloride (0.4 g, 82%).The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 2-(4-chlorophenyl)-2-(piperidin-4-yl)ethanolhydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.93-1.06 (m, 1H) 1.12-1.37 (m, 3H)1.54-1.67 (m, 1H) 1.89-1.99 (m, 1H) 2.06-2.15 (m, 1H) 2.18-2.26 (m, 4H)2.32 (s, 3H) 3.44-3.51 (m, 1H) 3.55-3.68 (m, 3H) 4.50-4.55 (m, 1H)7.16-7.22 (m, 2H) 7.28-7.35 (m, 2H) 13.04 (s, 1H)

MS: ES+ 398

Example 1011-(4-Chlorophenyl)-1-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol

Methylmagnesium bromide (3M in ether) (3.09 mL, 9.26 mmol) was addedslowly to a solution of tert-butyl4-(4-chlorobenzoyl)piperidine-1-carboxylate (Intermediate 40, 0.5 g,1.544 mmol) in THF (10 mL) at 0° C. under nitrogen. The reaction wasstirred at room temperature for 2 hours. The reaction was quenched with2M HCl and partitioned between ethyl acetate and 2M HCl. The phases wereseparated and the aqueous phase was extracted with ethyl acetate. Thecombined organics were washed with saturated brine, dried (phaseseparator) and concentrated in vacuo to afford tert-butyl4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (0.481 g,1.415 mmol, 92% yield) as a colourless oil. MS: ES-338.

Hydrogen chloride (4M in dioxane) (0.309 mL, 1.236 mmol) was added to asolution of tert-butyl4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (0.21 g,0.618 mmol) in methanol (10 mL). The reaction was stirred at roomtemperature overnight. The solution was concentrated and azeotroped withtoluene to give 1-(4-chlorophenyl)-1-(piperidin-4-yl)ethanolhydrochloride as a white solid (quantitative, MS: ES+ 240).

The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 1-(4-chlorophenyl)-1-(piperidin-4-yl)ethanolhydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.15-1.33 (m, 3H) 1.37 (s, 3H) 1.43-1.54(m, 1H) 1.66-1.77 (m, 1H) 2.01-2.20 (m, 2H) 2.27 (s, 6H) 3.48-3.66 (m,2H) 4.95 (s, 1H) 7.31-7.35 (m, 2H) 7.36-7.41 (m, 2H) 13.00 (br. s., 1H)

MS: ES+ 398

Example 1024-(1-(4-Chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

p-Toluenesulfonic acid monohydrate (0.963 g, 5.06 mmol) was added to asolution of tert-butyl4-(1-(4-chlorophenyl)-1-hydroxyethyl)piperidine-1-carboxylate (describedin the preparation of Example 101), (0.43 g, 1.265 mmol) in toluene (15mL) under nitrogen. Magnesium sulfate was added and the reaction washeated to reflux for 5 hours then cooled overnight. The reaction wasquenched with 2M NaOH and the mixture was partitioned between ethylacetate and water. The phases were separated and the aqueous extractedwith ethyl acetate, the combined organics were washed with saturatedbrine, dried (phase separator) and concentrated in vacuo to give crude4-(1-(4-chlorophenyl)ethylidene)-piperidine 4-methylbenzenesulfonate.Triethylamine (0.386 mL, 2.77 mmol) was added to a suspension of crude4-(1-(4-chlorophenyl)ethylidene)piperidine 4-methylbenzenesulfonate(0.364 g, 0.924 mmol) and 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3, 0.216 g, 1.109 mmol) in dichloromethane (10 mL). Thereaction was stirred at room temperature for 4 hours. The mixture wasdiluted with DCM, washed with water, dried (phase separator) andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluted with 0-100% ethyl acetate/petroleumether, then by reverse phase preparative HPLC eluted withacetonitrile/water (with 0.1% ammonia) to afford4-(1-(4-chlorophenyl)ethylidene)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine.This was then taken in a flask with platinum(IV) oxide (3.47 mg, 0.015mmol) and evacuated and purged with nitrogen three times. Ethanol (0.5mL) and ethyl acetate (0.5 mL) were added under vacuum, then thesuspension was stirred under an atmosphere of hydrogen for 1 hour. Thesuspension was filtered through diatomaceous earth and the filtrateconcentrated in vacuo. The crude product was purified by reverse phasepreparative HPLC eluted with acetonitrile/water (with 0.1% ammonia) toafford4-(1-(4-chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(0.024 g, 0.063 mmol, 41.2% yield) as a white foam.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.97-1.09 (m, 1H) 1.11-1.22 (m, 4H)1.27-1.43 (m, 2H) 1.84-1.92 (m, 1H) 2.06-2.15 (m, 1H) 2.16-2.25 (m, 1H)2.26-2.31 (m, 7H) 3.45-3.66 (m, 2H) 7.16-7.21 (m, 2H) 7.30-7.34 (m, 2H)12.99 (br. s, 1H)

MS: ES+ 382

Example 103N-(4-Chlorophenyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and N-(4-chlorophenyl)piperidin-4-amine hydrochloride.

¹H NMR (400 MHz, MeOD-d₆) δ ppm 1.32-1.45 (m, 4H) 2.10-2.18 (m, 2H) 2.45(s, 6H) 2.67-2.80 (m, 2H) 3.62-3.71 (m, 2H,) 4.10 (s, 1H) 6.54-6.61 (m,2H) 7.08-7.12 (m, 2H)

MS: ES+ 369

Example 1044-((4-Chlorophenyl)(ethoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-((4-chlorophenyl)(ethoxy)methyl)piperidinehydrochloride (Intermediate 46).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.10 (m, 3H) 1.16-1.30 (m, 3H) 1.49(br. s., 1H) 1.90-1.97 (m, 1H) 2.10-2.24 (m, 2H) 2.24-2.31 (m, 6H)3.18-3.26 (m, 2H) 3.48-3.63 (m, 2H) 3.99-4.04 (m, 1H) 7.23-7.28 (m, 2H)7.37-7.43 (m, 2H) 13.00 (br. s., 1H)

MS: ES+ 412

Example 1054-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-((4-chlorophenyl)fluoromethyl)piperidinehydrochloride (Intermediate 47).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H)2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H)7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

MS: ES+ 386

Example 1064-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidineEnantiomer A

4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 105) was separated into its enantiomers by supercritical fluidchromatography using a Chiralpak AD 20×250 mm 5 μm column eluting with20% methanol to afford4-((4-chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer A, as the first eluting peak.

e.e. 97.9%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H)2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H)7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

MS: ES+ 386

Example 1074-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidineEnantiomer B

4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine(Example 105) was separated into its enantiomers by supercritical fluidchromatography using a Chiralpak AD 20×250 mm 5 μm column eluting with20% methanol to afford4-((4-chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Enantiomer B, as the second eluting peak.

e.e. 98.1%

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.22-1.41 (m, 3H) 1.79-1.91 (m, 2H)2.17-2.25 (m, 1H) 2.29 (s, 7H) 3.52-3.67 (m, 2H) 5.23-5.41 (m, 1H)7.32-7.38 (m, 2H) 7.43-7.49 (m, 2H) 13.0 (br. s, 1H)

MS: ES+ 386

Example 1084-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol

tert-Butyl 4-(4-chlorobenzyl)-4-hydroxypiperidine-1-carboxylate wasprepared as described for tert-butyl4-(3,4-dichlorobenzyl)-4-hydroxypiperidine-1-carboxylate (Intermediate22). Hydrogen chloride (4M in dioxane) (0.609 mL, 2.437 mmol) was addedto a solution of tert-butyl4-(4-chlorobenzyl)-4-hydroxypiperidine-1-carboxylate (0.25 g, 0.767mmol) in methanol (5 mL). The reaction was stirred at room temperatureovernight, then concentrated and azeotroped with toluene to afford4-(4-chlorobenzyl)piperidin-4-ol hydrochloride (quantitative). The titlecompound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(4-chlorobenzyl)piperidin-4-ol hydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.36-1.45 (m, 2H) 1.46-1.60 (m, 2H) 2.29(br. s., 6H) 2.51-2.58 (m, 2H) 2.65 (s, 2H) 3.31-3.37 (m, 2H) 4.33 (s,1H) 7.17-7.25 (m, 2H) 7.27-7.34 (m, 2H) 13.02 (br. s., 1H)

MS: ES+ 384

Example 1094-(1-(4-Chlorophenyl)-2-methoxyethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Sodium hydride (0.046 g, 1.94 mmol) was added to a solution oftert-butyl 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate(Intermediate 45, 0.6 g, 1.76 mmol) in THF (15 mL). The reaction washeated to 60-65° C. for 2 hours then cooled to room temperature. Methyliodide (0.276 g, 1.94 mmol) and HMPA (0.3 mL) were added and thereaction was refluxed for 15 hours. The reaction was quenched withice/water and extracted with ethyl acetate. The combined organics weredried (sodium sulfate) and concentrated in vacuo. The crude product waspurified by column chromatography on silica, eluted with 0-70% ethylacetate/n-hexane to afford tert-butyl4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine-1-carboxylate (0.35 g,56%). This was taken up into dioxane (1 mL), treated with HCl/dioxane (7mL) and stirred at room temperature overnight. The reaction wasconcentrated in vacuo and triturated with diethyl ether to afford4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidine hydrochloride (0.2 g,80%). The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(1-(4-chlorophenyl)-2-hydroxyethyl)piperidinehydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 0.95-1.10 (m, 1H) 1.15-1.36 (m, 3H)1.51-1.64 (m, 1H) 1.85-1.94 (m, 1H) 2.06-2.15 (m, 1H) 2.23 (br. s., 3H)2.32 (br. s., 3H) 2.58-2.70 (m, 1H) 3.15 (s, 3H) 3.44-3.51 (m, 1H)3.51-3.56 (m, 2H) 3.57-3.64 (m, 1H) 7.17-7.23 (m, 2H) 7.30-7.35 (m, 2H)13.03 (br. s., 1H) MS: ES+ 412

Example 1101-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(methoxy(phenyl)methyl)piperidine

Prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(methoxy(phenyl)methyl)piperidine hydrochloride(prepared as described for 4-((4-Chlorophenyl)(methoxy)methyl)piperidinehydrochloride (Intermediate 43) using phenyl(piperidin-4-yl)methanonehydrochloride).

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.11-1.31 (m, 3H) 1.48-1.60 (m, 1H) 1.90(m, 1H) 2.08-2.24 (m, 2H) 2.27 (s, 6H) 3.06 (s, 3H) 3.47-3.63 (m, 2H)3.84-3.90 (m, 1H) 7.19-7.25 (m, 2H) 7.25-7.31 (m, 1H) 7.32-7.38 (m, 2H)13.01 (br. s, 1H)

MS: ES+ 364

Example 1114-(1-(4-Chlorophenyl)-2,2-difluoroethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine

Diethylaminosulfur trifluoride (0.242 mL, 1.835 mmol) was added to asolution of tert-butyl4-(1-(4-chlorophenyl)-2-oxoethyl)piperidine-1-carboxylate (Intermediate44, 0.31 g, 0.918 mmol) in DCM (5 mL) under nitrogen at −78° C. Thereaction was stirred at −78° C. for 2 hours, then warmed to roomtemperature overnight. A further portion of diethylaminosulfurtrifluoride (0.242 mL, 1.835 mmol) was added and the reaction stirred atroom temperature overnight. The reaction was quenched with saturatedsodium hydrogen carbonate. The aqueous was extracted with DCM andcombined organics were washed with water, dried (phase separator) andconcentrated in vacuo. The crude product was purified by columnchromatography on silica, eluted with 0-20% ethyl acetate/petroleumether to afford tert-butyl4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine-1-carboxylate (0.09g, 0.250 mmol, 27.3% yield) as a colourless oil. Hydrogen chloride (4Min dioxane) (0.125 mL, 0.500 mmol) was added to a solution of tert-butyl4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine-1-carboxylate (0.09g, 0.250 mmol) in methanol (5 mL). The reaction was stirred at roomtemperature overnight. The solution was concentrated in vacuo andazeotroped with toluene to give4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidine hydrochloride(quantitative) as a colourless oil that was used without furtherpurification. The title compound was prepared as described for4-(3,4-dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine(Example 1) from 3,5-dimethyl-1H-pyrazole-4-sulfonyl chloride(Intermediate 3) and 4-(1-(4-chlorophenyl)-2,2-difluoroethyl)piperidinehydrochloride.

¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.01-1.15 (m, 1H) 1.26-1.40 (m, 2H)1.77-1.90 (m, 1H) 1.94-2.04 (m, 1H) 2.13-2.22 (m, 1H) 2.28 (s, 7H)2.96-3.10 (m, 1H) 3.44-3.65 (m, 2H) 6.22-6.55 (m, 1H) 7.24-7.30 (m, 2H)7.38-7.43 (m, 2H) 13.02 (br. s., 1H)

MS: ES+ 418

3. BIOLOGICAL ASSAY

Prokineticin receptor 1 (PKR1) antagonists may be functionally assessedby measurement of change in intracellular calcium levels induced by Gqmediated increase in inositol triphosphate (IP3) levels. The ability ofa compound to block the intracellular release of calcium mediated by PK1in RBL2H3 cells expressing human PKR1 receptors is determined as ameasure of the compound's antagonist activity in vitro.

Approximately 10,000 cells per assay well are seeded in normal culturemedium in a 384 well plate (Corning). Twenty-four hours after seeding,the cells are loaded with a calcium sensitive fluorescent dye byreplacing the culture medium with assay buffer (lx Hanks bufferedsaline, 25 mM HEPES, 0.1% w/v fatty acid free BSA (bovine serumalbumin), pH 7.4) containing 1 mM probenecid and 1× Calcium 5 Reagent(Molecular Devices). Cells are incubated at 37° C. for 1 hour to allowfor dye uptake.

To test for antagonist activity, test compounds at a final concentrationrange between 0.32 nM-10 μM (diluted in assay buffer) are added to theassay wells and allowed to incubate for 10 minutes prior to stimulationwith PK1. After incubation with test compounds the assay plate is placedin a FLIPR Tetra (Molecular Devices) and PK1 (diluted in assay buffer)is added at the determined EC80 concentration (final). Ligand-dependentchanges in intracellular calcium levels are determined by measuringchanges in fluorescence of the dye at 525 nM following excitation at 485nM. Readings from wells that do not contain antagonist enable percentageinhibition curves to be plotted using 4-parameter fit algorithm and IC50values are calculated for each test compound.

Results

Compound of Compound of Example No. Mean IC₅₀ (μM) Example No. Mean IC₅₀(μM) 1 1.4 2 1 3 1.4 4 0.82 5 0.53 6 2.2 7 7.3 8 1.45 9 2.3 10 1.7 110.86 12 4.7 13 0.79 14 0.47 15 2.9 16 4.6 17 3.6 18 7 19 5.6 20 3.6 212.1 22 1.18 23 0.22 24 1.5 25 1.3 26 1.7 27 5.6 28 0.32 29 1.1 30 0.5131 0.31 32 3.4 33 0.44 34 0.24 35 1.1 36 1.1 37 7.4 38 3.2 39 0.21 400.21 41 5.9 42 5.9 43 6.3 44 5.1 45 1.4 46 1 47 1.9 48 3.8 49 1 50 2.151 1.5 52 2.7 53 0.9 54 5.2 55 0.52 56 0.95 57 1.6 58 2.4 59 2.4 60 0.961 1.08 62 0.68 63 0.64 64 0.89 65 0.94 66 1.01 67 0.52 68 2.02 69 6.4770 8.62 71 0.78 72 0.44 73 0.20 74 0.17 75 6.98 76 3.73 77 3.19 78 0.0779 0.05 80 0.81 81 0.67 82 1.02 83 0.73 84 0.72 85 1.23 86 4.60 87 5.8888 0.20 89 0.41 90 0.17 91 0.14 92 1.85 93 0.61 94 1.74 95 0.71 96 0.0897 4.62 98 0.16 99 0.06 100 9.42 101 2.38 102 0.47 103 1.76 104 0.72 1050.41 106 4.00 107 0.31 108 1.64 109 1.86 110 3.01 111 0.34

The compounds tested above exhibit IC₅₀ values significantly less than10 μM, with the most potent compounds showing antagonist activity at theprokineticin receptor with IC₅₀ values <1 μM. Accordingly, the compoundsof the invention are expected to be useful in the prevention ortreatment of conditions in which prokineticin receptor modulation isimplicated.

In addition, the compounds of the present invention possess variouslyadvantageous pharmacological and/or toxicological profiles, when testedin a variety of standard tests for such parameters. For example, thecompounds of the invention exhibit one or more potentially usefulproperties for in vivo use, when characterised by pharmacological and/ortoxicological tests including: hERG interaction (which is an indicationof potential cardiotoxicity, and measures the effects of the compoundson the human ether-a-go-go-related gene, using for example thePatchXpress 7000A platform); CypP₄₅₀ interactions (which may be measuredin accordance with the FDA draft guidelines for drug interaction studies(study design, data analysis and implications for dosing and labeling)(September 2006), see www.fda.gov); phototoxicity (for example using aprotocol in accordance with assay details outlined in the OECDguidelines for testing of chemicals: 432 In Vitro 3T3 Neutral Red Uptakephototoxicity test, April 2004); determination of pharmacokineticparameters (for example following in vivo dosing via multiple routes,with plasma concentrations of compounds being determined from venousblood samples using an LC-MS/MS protocol); and in vivo receptoroccupancy (determined, for example, using protocols based on Medhurst etal., Journal of Pharmacology and Experimental Therapeutics, 2007, 321,1032). These standard tests for the characterisation of drug moleculesare well known to the skilled person.

1. A compound of formula (I)

or a pharmaceutically acceptable salt thereof for use in treating adisease or condition mediated by a prokineticin, wherein in formula (I)W, X, Y and Z each independently represent N, NH or CH, with the provisothat W, X, Y and Z do not each simultaneously represent a moiety CH; mis 0, 1, 2 or 3; each R¹ independently represents halogen, cyano, C₁-C₆alkoxy, C₁-C₆ alkoxycarbonyl, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ alkylcarbonyl, or C₁-C₆ alkyl optionally substituted bycarboxyl or C₁-C₆ alkoxycarbonyl; n is 0, 1, 2, 3 or 4; each R²independently represents halogen, cyano, carboxyl, hydroxyl, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆ alkyl or a 5- to 9-memberedheterocyclic ring system; R³ represents an oxygen or sulphur atom, or agroup C═O, NR⁵ or CR⁶R⁷; R⁵ represents a hydrogen atom or a C₁-C₆ alkylgroup; R⁶ and R⁷ each independently represent a hydrogen or halogen atomor cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆alkyl or a 5- to 9-membered heterocyclic ring system; R⁴ represents a 6-to 10-membered aromatic or heteroaromatic ring system, the ring systemitself being optionally substituted by at least one substituent selectedfrom halogen, hydroxyl, cyano, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulphinyl, C₁-C₆ alkylsulphonyl,C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonyloxy, C₁-C₆ alkoxycarbonyl,amino, —CON(R⁸)₂, C₁-C₆ alkylamino, di-(C₁-C₆ alkyl)amino, C₃-C₆cycloalkyl, C₃-C₆ cycloalkyloxy or C₃-C₆ cycloalkylmethyl; and each R⁸independently represents a hydrogen atom or a C₁-C₆ alkyl group.
 2. Acompound according to claim 1, wherein the disease or condition ismediated by prokineticin
 1. 3. A compound according to claim 1 for usein treating schizophrenia, schizophreniform disorder, schizoaffectivedisorder, cognitive disorders or pain.
 4. A compound of formula (Ia) ora pharmaceutically acceptable salt thereof

wherein W¹, X¹, Y¹ and Z¹ each independently represent N, NH or CH, withthe proviso that W¹, X¹, Y¹ and Z¹ do not each simultaneously representa moiety CH; p is 0, 1, 2 or 3; each R¹¹ independently representshalogen, cyano, C₁-C₆ alkoxy, C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆alkylthio, C₁-C₆ alkylcarbonyl, or C₁-C₆ alkyl optionally substituted bycarboxyl or C₁-C₆ alkoxycarbonyl; q is 0, 1, 2, 3 or 4; each R¹²independently represents halogen, cyano, carboxyl, hydroxyl, C₁-C₆alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆ alkyl or a 5- to 9-memberedheterocyclic ring system; R¹³ represents an oxygen atom, or a group C═O,NR¹⁵ or CR¹⁶R¹⁷, with the provisos that (i) when R¹³ represents CO or NHand ring A represents pyrazol-4-yl or imidazol-4-yl, then p must be 3and R¹⁴ represents a substituted 6- to 10-membered aromatic orheteroaromatic ring system, and (ii) when R¹³ represents CH₂ and ring Arepresents pyrazol-4-yl or imidazol-4-yl, then either p is 3, or, p is 2and q is at least 1; R¹⁵ represents a hydrogen atom or a C₁-C₆ alkylgroup; R¹⁶ and R¹⁷ each independently represent a hydrogen or halogenatom or cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆alkyl or a 5- to 9-membered heterocyclic ring system; R¹⁴ represents a6- to 10-membered aromatic or heteroaromatic ring system, the ringsystem itself being optionally substituted by at least one substituentselected from halogen, hydroxyl, cyano, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl,C₂-C₆ alkynyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulphinyl, C₁-C₆ alkylsulphonyl,C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonyloxy, C₁-C₆ alkoxycarbonyl,amino, —CON(R¹⁸)₂, C₁-C₆ alkylamino, di-(C₁-C₆ alkyl)amino, C₃-C₆cycloalkyl, C₃-C₆ cycloalkyloxy or C₃-C₆ cycloalkylmethyl; and each R¹⁸independently represents a hydrogen atom or a C₁-C₆ alkyl group; butexcluding the following compounds: 1)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,2)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-fluorophenoxyl)piperidine,3)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methoxyphenoxyl)piperidine,4) 1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenoxypiperidine, 5)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(3-ethylphenoxyl)piperidine,6) 4-phenoxy-1-(1H-pyrazol-4-ylsulfonyl)piperidine, 7)4-(3-chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,8)[1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-methoxyphenyl)methanone,9)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2-methylphenoxyl)piperidine,10)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[[2-(trifluoromethyl)phenyl]methyl]-4-piperidinemethanol,11)1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinecarboxylicacid, ethyl ester, 12)4-[[1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl]oxy]benzonitrile,13)N-(2-methylphenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidineamine,14)1-[[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl]-4-(4-fluorophenoxyl)piperidine,15)4-(3-fluorophenoxy)-1-[(3-methyl-1-propyl-1H-pyrazol-4-yl)sulfonyl]piperidine,16)1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(2-fluorophenoxyl)piperidine,17)1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,18)1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(phenylmethyl)piperidine,19)1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,20)(4-(4-Methoxybenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,21)(4-(4-Chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,22)1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinemethanol,23)4-(phenylmethyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,24)[1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-fluorophenyl)methanone,and 25)2-[[1-[3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl]oxy]pyrazine.5. A compound according to claim 4, wherein at least two of W¹, X¹, Y¹and Z¹ represent N or NH.
 6. A compound according to claim 4 or claim 5,wherein p is 2 or
 3. 7. A compound according to any one of claims 4 to6, wherein each R¹¹ independently represents halogen, C₁-C₆ haloalkyl orC₁-C₆ alkyl.
 8. A compound according to any one of claims 4 to 7,wherein q is 0 or
 1. 9. A compound according to any one of claims 4 to8, wherein each R¹² independently represents halogen, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl or C₁-C₆ alkoxyC₁-C₆alkyl.
 10. A compound according to any one of claims 4 to 9, wherein R¹³represents an oxygen atom.
 11. A compound according to any one of claims4 to 9, wherein R¹³ represents NR¹⁵.
 12. A compound according to any oneof claims 4 to 9, wherein R¹³ represents CR¹⁶R¹⁷.
 13. A compoundaccording to claim 12, wherein R¹⁶ and R¹⁷ each independently representa hydrogen atom or a C₁-C₆ alkyl group.
 14. A compound according to anyone of claims 4 to 13, wherein R¹⁴ represents a 6- to 10-memberedaromatic or heteroaromatic ring system, the ring system itself beingoptionally substituted by at least one substituent selected fromhalogen, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆haloalkoxy.
 15. A compound according to claim 14, wherein theheteroaromatic ring system comprises from 1 to 4 ring heteroatomsindependently selected from nitrogen and oxygen.
 16. A compoundaccording to any one of the preceding claims being selected from:4-(3,4-Dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(3,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-[4-(Trifluoromethoxy)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Methylphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(3-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-({1-[(1,3,5-Trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}oxy)benzonitrile,4-(4-Chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,1-{[1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-(4-methylphenoxyl)piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,4-[4-(Trifluoromethyl)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Bromo-2-fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-chlorophenoxyl)piperidine,4-(4-Chlorophenoxy)-1-{[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(3-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-Phenoxy-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-3-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(Naphthalen-2-yloxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-2-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2,4-dichlorophenoxyl)piperidine,4-(2,4-Dichlorophenoxy)-1-{[1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(2,4-Dichlorophenoxy)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(4-Chloro-2-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,5-Chloro-2-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine,1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(naphthalen-2-yloxy)piperidine,5-Chloro-2-{[1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,4-(4-Chloro-2-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(2,4-Dichlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,4-(4-Chlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(2,6-dimethylphenoxyl)piperidine,4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(3-fluoro-4-methoxyphenoxy)piperidine,4-(3,5-Difluoro-4-methoxyphenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(3-Fluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(3,5-Difluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-3-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-2,6-difluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-3-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,5-Chloro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,(3,4-Dichlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,N-(4-Chlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,N-(3,4-Dichlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,4-Chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,3,4-Dichloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(2,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chlorobenzyl)-4-(methoxymethyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Ethyl4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,Ethyl4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,Ethyl4-(4-bromobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,4-(2,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,1-((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(4chlorobenzyl)piperidine,4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(3,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-3-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxyphenoxy)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxyphenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(2-fluorophenoxyl)piperidine,5-Chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,4-(4-Chloro-2-fluorobenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,5-Chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,5-Chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-methoxypyridine,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-methoxypiperidine,4-(4-Chloro-2-methoxybenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,4-(4-Chloro-2-methoxybenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,2-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,(4-Chlorophenyl)(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)(methoxy)methyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,1-(4-Chlorophenyl)-1-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,4-(1-(4-Chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)(ethoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(1-(4-Chlorophenyl)-2-methoxyethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(methoxy(phenyl)methyl)piperidine,4-(1-(4-Chlorophenyl)-2,2-difluoroethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,and pharmaceutically acceptable salts of any one thereof.
 17. A processfor the preparation of a compound of formula (Ia) as defined in claim 4or a pharmaceutically acceptable salt thereof which comprises (i)reacting a compound of formula

wherein L¹ represents a leaving group and p, W¹, X¹, Y¹, Z¹ and R¹¹ areas defined in formula (Ia), with a compound of formula

or a suitable salt thereof, wherein q, R¹², R¹³ and R¹⁴ are as definedin formula (Ia); or (ii) reacting a compound of formula

wherein L² represents a leaving group and p, q, W¹, X¹, Y¹, Z¹, R¹¹ andR¹² are as defined in formula (Ia), with a compound of formulaL³-R¹³—R¹⁴ (Va) wherein L³ represents a leaving group and R¹³ and R¹⁴are as defined in formula (Ia); and optionally thereafter carrying outone or more of the following procedures: converting a compound offormula (Ia) into another compound of formula (Ia) removing anyprotecting groups forming a pharmaceutically acceptable salt.
 18. Apharmaceutical composition comprising a compound according to any one ofclaims 4 to 16 in association with a pharmaceutically acceptableadjuvant, diluent or carrier, and optionally one or more othertherapeutic agents.
 19. A compound according to any one of claims 4 to16 for use in treating a disease or condition mediated by aprokineticin.
 20. A compound according to any one of claims 4 to 16 foruse in treating schizophrenia, schizophreniform disorder,schizoaffective disorder, cognitive disorders or pain.
 21. A compound offormula (Ia) or a pharmaceutically acceptable salt thereof,

wherein W¹, X¹, Y¹ and Z¹ each independently represent N, NH or CH,wherein at least two of W¹, X¹, Y¹ and Z¹ represent N or NH; p is 0, 1,2 or 3; each R¹¹ independently represents halogen, cyano, C₁-C₆ alkoxy,C₁-C₆ haloalkyl, C₁-C₆ haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylcarbonyl,or C₁-C₆ alkyl optionally substituted by carboxyl or C₁-C₆alkoxycarbonyl; q is 0, 1, 2, 3 or 4; each R¹² independently representshalogen, cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆ alkoxyC₁-C₆alkyl or a 5- to 9-membered heterocyclic ring system; R¹³ represents anoxygen atom, or a group C═O, NR¹⁵ or CR¹⁶R¹⁷, with the provisos that (i)when R¹³ represents CO or NH and ring A represents pyrazol-4-yl orimidazol-4-yl, then p must be 3 and R¹⁴ represents a substituted phenyl,pyridinyl or naphthyl ring system, and (ii) when R¹³ represents CH₂ andring A represents pyrazol-4-yl or imidazol-4-yl, then either p is 3, or,p is 2 and q is at least 1; R¹⁵ represents a hydrogen atom or a C₁-C₆alkyl group; R¹⁶ and R¹⁷ each independently represent a hydrogen orhalogen atom or cyano, carboxyl, hydroxyl, C₁-C₆ alkyl, C₁-C₆ haloalkyl,C₁-C₆ alkoxy, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxycarbonyl, C₁-C₆alkoxyC₁-C₆ alkyl or a 5- to 9-membered heterocyclic ring system; R¹⁴represents a phenyl, pyridinyl or naphthyl ring system, the ring systemitself being optionally substituted by at least one substituent selectedfrom halogen, hydroxyl, cyano, oxo, C₁-C₆ alkyl, C₂-C₆ alkenyl, C₂-C₆alkynyl, C₁-C₆ haloalkyl, C₁-C₆ hydroxyalkyl, C₁-C₆ alkoxy, C₁-C₆haloalkoxy, C₁-C₆ alkylthio, C₁-C₆ alkylsulphinyl, C₁-C₆ alkylsulphonyl,C₁-C₆ alkylcarbonyl, C₁-C₆ alkylcarbonyloxy, C₁-C₆ alkoxycarbonyl,amino, —CON(R¹⁸)₂, C₁-C₆ alkylamino, di-(C₁-C₆ alkyl)amino, C₃-C₆cycloalkyl, C₃-C₆ cycloalkyloxy or C₃-C₆ cycloalkylmethyl; and each R¹⁸independently represents a hydrogen atom or a C₁-C₆ alkyl group; butexcluding the following compounds:1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-fluorophenoxyl)piperidine,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methoxyphenoxyl)piperidine,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-phenoxypiperidine,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(3-ethylphenoxyl)piperidine,4-phenoxy-1-(1H-pyrazol-4-ylsulfonyl)piperidine,4-(3-chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,[1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-methoxyphenyl)methanone,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2-methylphenoxyl)piperidine,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[[2-(trifluoromethyl)phenyl]methyl]-4-piperidinemethanol,1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinecarboxylicacid, ethyl ester,4-[[1-[(1-methyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl]oxy]benzonitrile,N-(2-methylphenyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidineamine,1-[[1-(difluoromethyl)-3-methyl-1H-pyrazol-4-yl]sulfonyl]-4-(4-fluorophenoxyl)piperidine,4-(3-fluorophenoxy)-1-[(3-methyl-1-propyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(2-fluorophenoxyl)piperidine,1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,1-[[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl]-4-(phenylmethyl)piperidine,1-[(1-ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(phenylmethyl)piperidine,(4-(4-Methoxybenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,(4-(4-Chlorobenzyl)-1-(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[(4-methoxyphenyl)methyl]-4-piperidinemethanol,4-(phenylmethyl)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,[1-[(5-chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-piperidinyl](4-fluorophenyl)methanone,1-[(1-methyl-1H-imidazol-4-yl)sulfonyl]-4-(2-naphthalenyloxy)piperidine,4-((phenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,and 4-(phenylmethyl)-1-(1H-imidazol-5-ylsulfonyl)piperidine.
 22. Acompound according to claim 21, wherein p is 2 or
 3. 23. A compoundaccording to claim 21, wherein each R¹¹ independently representshalogen, C₁-C₆ haloalkyl or C₁-C₆ alkyl.
 24. A compound according toclaim 21, wherein q is 0 or
 1. 25. A compound according to claim 21,wherein each R¹² independently represents halogen, cyano, hydroxyl,C₁-C₆ alkyl, C₁-C₆ alkoxy, C₁-C₆ alkoxycarbonyl or C₁-C₆ alkoxyC₁-C₆alkyl.
 26. A compound according to claim 21, wherein R¹³ represents anoxygen atom.
 27. A compound according to claim 21, wherein R¹³represents NR¹⁵.
 28. A compound according to claim 21, wherein R¹³represents CR¹⁶R¹⁷.
 29. A compound according to claim 28, wherein R¹⁶and R¹⁷ each independently represent a hydrogen atom or a C₁-C₆ alkylgroup.
 30. A compound according to claim 21, wherein R¹⁴ represents aphenyl, pyridinyl or naphthyl ring system, the ring system itself beingoptionally substituted by at least one substituent selected fromhalogen, cyano, C₁-C₆ alkyl, C₁-C₆ haloalkyl, C₁-C₆ alkoxy and C₁-C₆haloalkoxy.
 31. A compound according to claim 21, selected from thegroup consisting of:4-(3,4-Dichlorophenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(3,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-[4-(Trifluoromethoxy)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Methylphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(3-Chlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-({1-[(1,3,5-Trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidin-4-yl}oxy)benzonitrile,4-(4-Chlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(1-Ethyl-3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,1-{[1,5-Dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}-4-(4-methylphenoxyl)piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-methylphenoxyl)piperidine,4-[4-(Trifluoromethyl)phenoxy]-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Bromo-2-fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(4-chlorophenoxyl)piperidine,4-(4-Chlorophenoxy)-1-{[1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(3-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Methoxyphenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-Phenoxy-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Fluorophenoxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-3-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(Naphthalen-2-yloxy)-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(4-Chlorophenoxy)-2-methyl-1-[(1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,1-[(5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(2,4-dichlorophenoxyl)piperidine,4-(2,4-Dichlorophenoxy)-1-{[1,3-dimethyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(2,4-Dichlorophenoxy)-1-[(1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-[(3,5-diethyl-1-methyl-1H-pyrazol-4-yl)sulfonyl]piperidine,4-(2,4-Dichlorophenoxy)-1-{[1-(difluoromethyl)-3,5-dimethyl-1H-pyrazol-4-yl]sulfonyl}piperidine,4-(4-Chloro-2-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,5-Chloro-2-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-[4-(trifluoromethoxy)phenoxy]piperidine,1-[(3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl]-4-(naphthalen-2-yloxy)piperidine,5-Chloro-2-{[1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]oxy}benzonitrile,4-(4-Chloro-2-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(2,4-Dichlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,4-(4-Chlorophenoxy)-1-(1,4-dimethyl-1H-pyrazole-5-sulfonyl)piperidine,1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(2,6-dimethylphenoxyl)piperidine,4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-[4-Chloro-2-(trifluoromethyl)phenoxy]-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,1-(3,5-Dimethyl-1H-pyrazole-4-sulfonyl)-4-(3-fluoro-4-methoxyphenoxy)piperidine,4-(3,5-Difluoro-4-methoxyphenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(3-Fluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(3,5-Difluoro-4-methoxyphenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-3-fluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-2,6-difluorophenoxy)-1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidine,4-(4-Chloro-3-fluorophenoxy)-1-(3,5-dimethyl-1H-pyrazole-4-sulfonyl)piperidine,5-Chloro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,(3,4-Dichlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanone,N-(4-Chlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,N-(3,4-Dichlorophenyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-amine,4-Chloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,3,4-Dichloro-N-{[1-(trimethyl-1H-pyrazole-4-sulfonyl)piperidin-4-yl]methyl}aniline,4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chlorobenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(2,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chlorobenzyl)-4-(methoxymethyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,Ethyl4-(4-chlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,Ethyl4-(4-bromobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,Ethyl4-(4-bromobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carboxylate,4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,4-(2,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine-4-carbonitrile,1-((5-Chloro-1,3-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(4chlorobenzyl)piperidine,4-(3,4-Dichlorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(3,4-Dichlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-3-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxyphenoxy)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxyphenoxy)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(2-fluorophenoxyl)piperidine,5-Chloro-3-fluoro-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,4-(4-Chloro-2-fluorobenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-fluorobenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,5-Chloro-3-methoxy-2-((1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)pyridine,5-Chloro-2-((1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)oxy)-3-methoxypyridine,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-methoxypiperidine,4-(4-Chloro-2-methoxybenzyl)-4-methoxy-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chloro-2-methoxybenzyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(4-Chloro-2-methoxybenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-fluoropiperidine,4-(4-Chloro-2-methoxybenzyl)-4-fluoro-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,2-(4-Chloro-2-fluorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)acetonitrile,(4-Chlorophenyl)(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,(4-Chlorophenyl)(1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)methanol,4-((4-Chlorophenyl)(methoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)(methoxy)methyl)-1-((1,3,5-trimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,2-(4-Chlorophenyl)-2-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,1-(4-Chlorophenyl)-1-(1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-yl)ethanol,4-(1-(4-Chlorophenyl)ethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)(ethoxy)methyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-((4-Chlorophenyl)fluoromethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,4-(4-Chlorobenzyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidin-4-ol,4-(1-(4-Chlorophenyl)-2-methoxyethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,1-((3,5-Dimethyl-1H-pyrazol-4-yl)sulfonyl)-4-(methoxy(phenyl)methyl)piperidine,4-(1-(4-Chlorophenyl)-2,2-difluoroethyl)-1-((3,5-dimethyl-1H-pyrazol-4-yl)sulfonyl)piperidine,and pharmaceutically acceptable salts of any one thereof.
 32. A processfor the preparation of a compound of formula (Ia) as defined in claim 21or a pharmaceutically acceptable salt thereof which comprises the stepof: (i) reacting a compound of formula (IIa),

wherein L¹ represents a leaving group and p, W¹, X¹, Y¹, Z¹ and R¹¹ areas defined in formula (Ia), with a compound of formula (IIIa)

or a suitable salt thereof, wherein q, R¹², R¹³ and R¹⁴ are as definedin formula (Ia); or (ii) reacting a compound of formula (IVa),

wherein L² represents a leaving group and p, q, W¹, X¹, Y¹, Z¹, R¹¹ andR¹² are as defined in formula (Ia), with a compound of formulaL³-R¹³—R¹⁴ (Va) wherein L³ represents a leaving group and R¹³ and R¹⁴are as defined in formula (Ia); and optionally further comprising one ormore of the following steps (iii) through (v) which may be carried outin any order: (iii) converting a compound of formula (Ia) into anothercompound of formula (Ia); (iv) removing any protecting groups; and/or(v) forming a pharmaceutically acceptable salt.
 33. A pharmaceuticalcomposition comprising a compound according to claim 21 in associationwith a pharmaceutically acceptable adjuvant, diluent or carrier, andoptionally one or more other therapeutic agents.
 34. A compoundaccording to claim 21 for use in treating a disease or conditionmediated by a prokineticin.
 35. A compound according to claim 21 for usein treating schizophrenia, schizophreniform disorder, schizoaffectivedisorder, cognitive disorders or pain.